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Marks, Jeffrey R.

Overview:

I have been engaged in basic and applied cancer research for over 28 years beginning with my post-doctoral fellowship under Arnold Levine at Princeton. Since being appointed to the faculty in the Department of Surgery at Duke, my primary interest has been towards understanding breast and ovarian cancer. I am a charter member of the NCI-Early Detection Research Network (EDRN) and have been an integral scientist in the breast and gynecologic collaborative group for 15 years including leading this group for a 5 year period. I am also a major contributor to the Cancer Genome Atlas and have worked in this context for the past 4 years. My research interests are in the molecular etiology of these diseases and understanding how key genetic events contribute to their onset and progression. My work has been very multi-disciplinary incorporating quantitative, population, genetic, and behavioral approaches.  I consider my specialty to be in the area of using human breast and ovarian cancer as the primary and only authentic model system to understand these diseases.  

Positions:

Associate Professor of Surgery

Surgery, Surgical Sciences
School of Medicine

Associate Professor of Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1985

Ph.D. — University of California at San Diego

Grants:

Breast Cancer Detection Consortium

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 19, 2016
End Date
August 31, 2021

Genomic Diversity and the Microenvironment as Drivers of Progression in DCIS

Administered By
Surgery, Advanced Oncologic and Gastrointestinal Surgery
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
September 30, 2014
End Date
September 29, 2020

Fibulin-3 as a Novel Biomarker and Trget in the Breast Tumor Microenvironment

Administered By
Medicine, Medical Oncology
AwardedBy
Susan G. Komen Breast Cancer Foundation
Role
Key Faculty
Start Date
December 01, 2015
End Date
November 30, 2018

(PQC3) Genomic Diversity and Microenvironment as Drivers of Metastasis in DCIS

Administered By
Surgery, Advanced Oncologic and Gastrointestinal Surgery
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 01, 2014
End Date
July 31, 2018

Can contrast dynamics in breast MRI predict genomic intra-tumor heterogeneity

Administered By
Radiology
AwardedBy
Bracco Diagnostics, Inc.
Role
Investigator
Start Date
July 18, 2016
End Date
June 30, 2018

Molecular and Radiologic Predictors of Invasion in a DCIS Active Surveillance Cohort

Administered By
Surgery, Advanced Oncologic and Gastrointestinal Surgery
AwardedBy
Breast Cancer Research Foundation
Role
Co Investigator
Start Date
October 01, 2016
End Date
September 30, 2017

A Simple System for Early Detection of Breast Cancer

Administered By
Surgery, Surgical Sciences
AwardedBy
Arizona State University
Role
Principal Investigator
Start Date
July 01, 2014
End Date
June 30, 2017

Gene expression programs of lactic acidosis in human cancers

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
July 02, 2007
End Date
April 30, 2017

Atlantic Breast and Gynecologic Clinical Validation Center

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 1999
End Date
June 30, 2016

Integrating Population and Basic Science in Cancer Research

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Advisor
Start Date
September 01, 2009
End Date
August 31, 2015

TCGA - Breast Cancer

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 29, 2010
End Date
March 31, 2015

Epidemiology of Ovarian Cancer in African-American Women

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
June 01, 2010
End Date
February 28, 2015

Integration of Oncogenic Networks in Cancer Phenotypes

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
September 30, 2004
End Date
February 28, 2011

MAL Promoter Hypermethylation and its Implications in Breast Cancer

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2007
End Date
June 30, 2010

Developing Biomarker-Based Prognostics in Breast Cancer

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
July 06, 2004
End Date
June 30, 2009

Biomarker Studies for Novel Anti-Cancer Agents

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
May 28, 2003
End Date
February 29, 2008

Improving genomic prediction models in breast cancer.

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
September 02, 2004
End Date
July 31, 2007

PPARy: Biomarker for Breast Cancer in Older Women

Administered By
Medicine, Geriatrics
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
August 01, 2005
End Date
March 31, 2007

Tissue Transglutaminase And Breast Cancer Biology

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 01, 1997
End Date
May 31, 2003

Characterization of BRCA2

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 19, 1908
End Date
March 31, 2002

Immune Response to Breast Ductal Carcinoma In Situ

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
September 01, 1992
End Date
August 31, 2000

Tissue Transglutaminase And Breast Cancer Biology

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
August 01, 1997
End Date
May 31, 1999

Characterization Of Brca2

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
June 01, 1997
End Date
March 31, 1999

Planning A Program Of Research In Early Breast Cancer

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 1994
End Date
September 29, 1998

Spore In Breast Cancer

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 1995
End Date
August 31, 1998

Spore In Breast Cancer

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 1995
End Date
August 31, 1998

Spore In Breast Cancer

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 1995
End Date
August 31, 1998

Surrogate Markers Of Tumor Specific Immunity

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
August 24, 1994
End Date
May 31, 1998

Molecularly-Defined Taa As Human Anti-Tumor Ctl Targets

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
August 01, 1993
End Date
July 31, 1997

Molecularly-Defined Taa As Human Anti-Tumor Ctl Targets

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
August 01, 1992
End Date
May 31, 1997

Molecularly-Defined Taa As Human Anti-Tumor Ctl Targets

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
June 01, 1992
End Date
May 31, 1997

Retinoid Signaling Defects In Breast Cancer

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 1996
End Date
April 30, 1997

Retinoid Signalling Defects In Breast Cancer

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 1993
End Date
April 30, 1997

P53 In Human Breast Cancer

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
May 01, 1993
End Date
April 30, 1995
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Publications:

The LINK-A lncRNA interacts with PtdIns(3,4,5)P3 to hyperactivate AKT and confer resistance to AKT inhibitors.

Phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3 or PIP3) mediates signalling pathways as a second messenger in response to extracellular signals. Although primordial functions of phospholipids and RNAs have been hypothesized in the 'RNA world', physiological RNA-phospholipid interactions and their involvement in essential cellular processes have remained a mystery. We explicate the contribution of lipid-binding long non-coding RNAs (lncRNAs) in cancer cells. Among them, long intergenic non-coding RNA for kinase activation (LINK-A) directly interacts with the AKT pleckstrin homology domain and PIP3 at the single-nucleotide level, facilitating AKT-PIP3 interaction and consequent enzymatic activation. LINK-A-dependent AKT hyperactivation leads to tumorigenesis and resistance to AKT inhibitors. Genomic deletions of the LINK-A PIP3-binding motif dramatically sensitized breast cancer cells to AKT inhibitors. Furthermore, meta-analysis showed the correlation between LINK-A expression and incidence of a single nucleotide polymorphism (rs12095274: A > G), AKT phosphorylation status, and poor outcomes for breast and lung cancer patients. PIP3-binding lncRNA modulates AKT activation with broad clinical implications.

Authors
Lin, A; Hu, Q; Li, C; Xing, Z; Ma, G; Wang, C; Li, J; Ye, Y; Yao, J; Liang, K; Wang, S; Park, PK; Marks, JR; Zhou, Y; Zhou, J; Hung, M-C; Liang, H; Hu, Z; Shen, H; Hawke, DH; Han, L; Zhou, Y; Lin, C; Yang, L
MLA Citation
Lin, A, Hu, Q, Li, C, Xing, Z, Ma, G, Wang, C, Li, J, Ye, Y, Yao, J, Liang, K, Wang, S, Park, PK, Marks, JR, Zhou, Y, Zhou, J, Hung, M-C, Liang, H, Hu, Z, Shen, H, Hawke, DH, Han, L, Zhou, Y, Lin, C, and Yang, L. "The LINK-A lncRNA interacts with PtdIns(3,4,5)P3 to hyperactivate AKT and confer resistance to AKT inhibitors." Nature cell biology (February 20, 2017).
PMID
28218907
Source
epmc
Published In
Nature Cell Biology
Publish Date
2017
DOI
10.1038/ncb3473

Can algorithmically assessed MRI features predict which patients with a preoperative diagnosis of ductal carcinoma in situ are upstaged to invasive breast cancer?

To assess the ability of algorithmically assessed magnetic resonance imaging (MRI) features to predict the likelihood of upstaging to invasive cancer in newly diagnosed ductal carcinoma in situ (DCIS).We identified 131 patients at our institution from 2000-2014 with a core needle biopsy-confirmed diagnosis of pure DCIS, a 1.5 or 3T preoperative bilateral breast MRI with nonfat-saturated T1 -weighted MRI sequences, no preoperative therapy before breast MRI, and no prior history of breast cancer. A fellowship-trained radiologist identified the lesion on each breast MRI using a bounding box. Twenty-nine imaging features were then computed automatically using computer algorithms based on the radiologist's annotation.The rate of upstaging of DCIS to invasive cancer in our study was 26.7% (35/131). Out of all imaging variables tested, the information measure of correlation 1, which quantifies spatial dependency in neighboring voxels of the tumor, showed the highest predictive value of upstaging with an area under the curve (AUC) = 0.719 (95% confidence interval [CI]: 0.609-0.829). This feature was statistically significant after adjusting for tumor size (P < 0.001).Automatically assessed MRI features may have a role in triaging which patients with a preoperative diagnosis of DCIS are at highest risk for occult invasive disease.4J. Magn. Reson. Imaging 2017.

Authors
Harowicz, MR; Saha, A; Grimm, LJ; Marcom, PK; Marks, JR; Hwang, ES; Mazurowski, MA
MLA Citation
Harowicz, MR, Saha, A, Grimm, LJ, Marcom, PK, Marks, JR, Hwang, ES, and Mazurowski, MA. "Can algorithmically assessed MRI features predict which patients with a preoperative diagnosis of ductal carcinoma in situ are upstaged to invasive breast cancer?." Journal of magnetic resonance imaging : JMRI (February 9, 2017).
PMID
28181348
Source
epmc
Published In
Journal of Magnetic Resonance Imaging
Publish Date
2017
DOI
10.1002/jmri.25655

Algorithms for prediction of the Oncotype DX recurrence score using clinicopathologic data: a review and comparison using an independent dataset.

Given the potential savings in cost and resource utilization, several algorithms have been proposed to predict Oncotype DX recurrence score (ODX RS) using commonly acquired histopathologic variables. Although it is promising, additional independent validation of these surrogate markers is needed prior to guide the patient management.In this retrospective study, we analyzed 305 patients with invasive breast cancer at our institution who had ODX RS available. We selected five equations that provide a surrogate measure of ODX as previously published by Klein et al. (Magee equations 1-3), Gage et al., and Tang et al. All equations used estrogen receptor status and progesterone receptor status along with different combinations of grade, proliferation indices (Ki-67, mitotic rate), HER2 status, and tumor size.Of all surrogate scores tested, the Magee equation 2 provided the highest correlation with ODX both with regard to raw score (Pearson's correlation coefficient = 0.66 95% CI 0.59-0.72) and categorical correlation (Cohen's kappa = 0.43, 95% CI 0.33-0.53). Although Magee equation 2 provided a way to reliably identify high-risk disease by assigning 95% of the patients with high ODX RS to either the intermediate- or high-risk group, it was unable to reliably identify the potential for patients to have intermediate- or high-risk disease by ODX (66% of such patients identified).Although commonly available surrogates for ODX appear to predict high-risk ODX RS, they are unable to reliably rule out the presence of patients with intermediate-risk disease by ODX. Given the potential benefit of adjuvant chemotherapy in women with intermediate-risk disease by ODX, current surrogates are unable to safely substitute for ODX. Characterizing the true recurrence risk in patients with intermediate-risk disease by ODX is critical to the clinical adoption of current surrogate markers and is an area of ongoing clinical trials.

Authors
Harowicz, MR; Robinson, TJ; Dinan, MA; Saha, A; Marks, JR; Marcom, PK; Mazurowski, MA
MLA Citation
Harowicz, MR, Robinson, TJ, Dinan, MA, Saha, A, Marks, JR, Marcom, PK, and Mazurowski, MA. "Algorithms for prediction of the Oncotype DX recurrence score using clinicopathologic data: a review and comparison using an independent dataset." Breast cancer research and treatment 162.1 (February 2017): 1-10.
PMID
28064383
Source
epmc
Published In
Breast Cancer Research and Treatment
Volume
162
Issue
1
Publish Date
2017
Start Page
1
End Page
10
DOI
10.1007/s10549-016-4093-4

PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.

The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

Authors
Southey, MC; Goldgar, DE; Winqvist, R; Pylkäs, K; Couch, F; Tischkowitz, M; Foulkes, WD; Dennis, J; Michailidou, K; van Rensburg, EJ; Heikkinen, T; Nevanlinna, H; Hopper, JL; Dörk, T; Claes, KB; Reis-Filho, J; Teo, ZL; Radice, P; Catucci, I; Peterlongo, P; Tsimiklis, H; Odefrey, FA; Dowty, JG; Schmidt, MK; Broeks, A; Hogervorst, FB; Verhoef, S; Carpenter, J; Clarke, C; Scott, RJ; Fasching, PA; Haeberle, L; Ekici, AB; Beckmann, MW; Peto, J; Dos-Santos-Silva, I; Fletcher, O; Johnson, N; Bolla, MK et al.
MLA Citation
Southey, MC, Goldgar, DE, Winqvist, R, Pylkäs, K, Couch, F, Tischkowitz, M, Foulkes, WD, Dennis, J, Michailidou, K, van Rensburg, EJ, Heikkinen, T, Nevanlinna, H, Hopper, JL, Dörk, T, Claes, KB, Reis-Filho, J, Teo, ZL, Radice, P, Catucci, I, Peterlongo, P, Tsimiklis, H, Odefrey, FA, Dowty, JG, Schmidt, MK, Broeks, A, Hogervorst, FB, Verhoef, S, Carpenter, J, Clarke, C, Scott, RJ, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Peto, J, Dos-Santos-Silva, I, Fletcher, O, Johnson, N, and Bolla, MK et al. "PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS." Journal of medical genetics 53.12 (December 2016): 800-811.
PMID
27595995
Source
epmc
Published In
Journal of medical genetics
Volume
53
Issue
12
Publish Date
2016
Start Page
800
End Page
811
DOI
10.1136/jmedgenet-2016-103839

Abstract 3407: Gene expression subtypes of high grade serous ovarian cancer in African American women

Authors
Doherty, JA; Greene, CS; Rudd, JE; Tafe, LJ; Alberg, AJ; Bandera, EV; Barnholtz-Sloan, J; Bondy, M; Cote, ML; Funkhouser, E; Moorman, PG; Peters, ES; Schwartz, AG; Terry, P; Bentley, R; Berchuck, A; Marks, JR; Schildkraut, JM
MLA Citation
Doherty, JA, Greene, CS, Rudd, JE, Tafe, LJ, Alberg, AJ, Bandera, EV, Barnholtz-Sloan, J, Bondy, M, Cote, ML, Funkhouser, E, Moorman, PG, Peters, ES, Schwartz, AG, Terry, P, Bentley, R, Berchuck, A, Marks, JR, and Schildkraut, JM. "Abstract 3407: Gene expression subtypes of high grade serous ovarian cancer in African American women." July 15, 2016.
Source
crossref
Published In
Cancer Research
Volume
76
Issue
14 Supplement
Publish Date
2016
Start Page
3407
End Page
3407
DOI
10.1158/1538-7445.AM2016-3407

Circulating Cancer-Associated Macrophage-Like Cells Differentiate Malignant Breast Cancer and Benign Breast Conditions.

Blood-based testing can be used as a noninvasive method to recover and analyze circulating tumor-derived cells for clinical use. Circulating cancer-associated macrophage-like cells (CAML) are specialized myeloid cells found in peripheral blood and associated with the presence of solid malignancies. We measured CAMLs prospectively in peripheral blood to ascertain their prevalence, specificity, and sensitivity in relation to breast disease status at clinical presentation.We report on two related but separate studies: 1) CellSieve microfilters were used to isolate CAMLs from blood samples of patients with known malignant disease (n = 41). Prevalence and specificity was compared against healthy volunteers (n = 16). 2) A follow-up double-blind pilot study was conducted on women (n = 41) undergoing core-needle biopsy to diagnose suspicious breast masses.CAMLs were found in 93% of known malignant patients (n = 38/41), averaging 19.4 cells per sample, but none in the healthy controls. In subjects undergoing core biopsy for initial diagnosis, CAMLs were found in 88% of subjects with invasive carcinoma (n = 15/17) and 26% with benign breast conditions (n = 5/19).These preliminary pilot studies suggest that the presence of CAMLs may differentiate patients with malignant disease, benign breast conditions, and healthy individuals.We supply evidence that this previously unidentified circulating stromal cell may have utility as a screening tool to detect breast cancer in various malignancies, irrespective of disease stage. Cancer Epidemiol Biomarkers Prev; 25(7); 1037-42. ©2016 AACR.

Authors
Adams, DL; Adams, DK; Alpaugh, RK; Cristofanilli, M; Martin, SS; Chumsri, S; Tang, C-M; Marks, JR
MLA Citation
Adams, DL, Adams, DK, Alpaugh, RK, Cristofanilli, M, Martin, SS, Chumsri, S, Tang, C-M, and Marks, JR. "Circulating Cancer-Associated Macrophage-Like Cells Differentiate Malignant Breast Cancer and Benign Breast Conditions." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 25.7 (July 2016): 1037-1042.
PMID
27197300
Source
epmc
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
25
Issue
7
Publish Date
2016
Start Page
1037
End Page
1042
DOI
10.1158/1055-9965.epi-15-1221

Outcomes of Active Surveillance for Ductal Carcinoma in Situ: A Computational Risk Analysis.

Ductal carcinoma in situ (DCIS) is a noninvasive breast lesion with uncertain risk for invasive progression. Usual care (UC) for DCIS consists of treatment upon diagnosis, thus potentially overtreating patients with low propensity for progression. One strategy to reduce overtreatment is active surveillance (AS), whereby DCIS is treated only upon detection of invasive disease. Our goal was to perform a quantitative evaluation of outcomes following an AS strategy for DCIS.Age-stratified, 10-year disease-specific cumulative mortality (DSCM) for AS was calculated using a computational risk projection model based upon published estimates for natural history parameters, and Surveillance, Epidemiology, and End Results data for outcomes. AS projections were compared with the DSCM for patients who received UC. To quantify the propagation of parameter uncertainty, a 95% projection range (PR) was computed, and sensitivity analyses were performed.Under the assumption that AS cannot outperform UC, the projected median differences in 10-year DSCM between AS and UC when diagnosed at ages 40, 55, and 70 years were 2.6% (PR = 1.4%-5.1%), 1.5% (PR = 0.5%-3.5%), and 0.6% (PR = 0.0%-2.4), respectively. Corresponding median numbers of patients needed to treat to avert one breast cancer death were 38.3 (PR = 19.7-69.9), 67.3 (PR = 28.7-211.4), and 157.2 (PR = 41.1-3872.8), respectively. Sensitivity analyses showed that the parameter with greatest impact on DSCM was the probability of understaging invasive cancer at diagnosis.AS could be a viable management strategy for carefully selected DCIS patients, particularly among older age groups and those with substantial competing mortality risks. The effectiveness of AS could be markedly improved by reducing the rate of understaging.

Authors
Ryser, MD; Worni, M; Turner, EL; Marks, JR; Durrett, R; Hwang, ES
MLA Citation
Ryser, MD, Worni, M, Turner, EL, Marks, JR, Durrett, R, and Hwang, ES. "Outcomes of Active Surveillance for Ductal Carcinoma in Situ: A Computational Risk Analysis." Journal of the National Cancer Institute 108.5 (May 2016).
PMID
26683405
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
108
Issue
5
Publish Date
2016
DOI
10.1093/jnci/djv372

Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility.

The signaling events that drive familial breast cancer (FBC) risk remain poorly understood. While the majority of genomic studies have focused on genetic risk variants, known risk variants account for at most 30% of FBC cases. Considering that multiple genes may influence FBC risk, we hypothesized that a pathway-based strategy examining different data types from multiple tissues could elucidate the biological basis for FBC. In this study, we performed integrated analyses of gene expression and exome-sequencing data from peripheral blood mononuclear cells and showed that cell adhesion pathways are significantly and consistently dysregulated in women who develop FBC. The dysregulation of cell adhesion pathways in high-risk women was also identified by pathway-based profiling applied to normal breast tissue data from two independent cohorts. The results of our genomic analyses were validated in normal primary mammary epithelial cells from high-risk and control women, using cell-based functional assays, drug-response assays, fluorescence microscopy, and Western blotting assays. Both genomic and cell-based experiments indicate that cell-cell and cell-extracellular matrix adhesion processes seem to be disrupted in non-malignant cells of women at high risk for FBC and suggest a potential role for these processes in FBC development.

Authors
Piccolo, SR; Hoffman, LM; Conner, T; Shrestha, G; Cohen, AL; Marks, JR; Neumayer, LA; Agarwal, CA; Beckerle, MC; Andrulis, IL; Spira, AE; Moos, PJ; Buys, SS; Johnson, WE; Bild, AH
MLA Citation
Piccolo, SR, Hoffman, LM, Conner, T, Shrestha, G, Cohen, AL, Marks, JR, Neumayer, LA, Agarwal, CA, Beckerle, MC, Andrulis, IL, Spira, AE, Moos, PJ, Buys, SS, Johnson, WE, and Bild, AH. "Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility." Molecular systems biology 12.3 (March 10, 2016): 860-.
PMID
26969729
Source
epmc
Published In
Molecular systems biology
Volume
12
Issue
3
Publish Date
2016
Start Page
860
DOI
10.15252/msb.20156506

Abstract P4-09-16: A monoclonal antibody with exceptional specificity across major breast cancer subtypes

Authors
Das Roy, L; Zhou, R; Dillon, L; Moore, LJ; Puri, R; Marks, JR; Lyerly, HK; Mukherjee, P
MLA Citation
Das Roy, L, Zhou, R, Dillon, L, Moore, LJ, Puri, R, Marks, JR, Lyerly, HK, and Mukherjee, P. "Abstract P4-09-16: A monoclonal antibody with exceptional specificity across major breast cancer subtypes." February 15, 2016.
Source
crossref
Published In
Cancer Research
Volume
76
Issue
4 Supplement
Publish Date
2016
Start Page
P4-09-16
End Page
P4-09-16
DOI
10.1158/1538-7445.SABCS15-P4-09-16

Abstract P6-05-03: Genomic diversity of ductal carcinoma in situ (DCIS) as a driver of invasion and metastasis

Authors
King, LM; Marks, JR; Hall, AH; Temko, D; Graham, TA; Mardis, ER; Maley, CC; Hwang, E
MLA Citation
King, LM, Marks, JR, Hall, AH, Temko, D, Graham, TA, Mardis, ER, Maley, CC, and Hwang, E. "Abstract P6-05-03: Genomic diversity of ductal carcinoma in situ (DCIS) as a driver of invasion and metastasis." February 15, 2016.
Source
crossref
Published In
Cancer Research
Volume
76
Issue
4 Supplement
Publish Date
2016
Start Page
P6-05-03
End Page
P6-05-03
DOI
10.1158/1538-7445.SABCS15-P6-05-03

The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer.

Although long non-coding RNAs (lncRNAs) predominately reside in the nucleus and exert their functions in many biological processes, their potential involvement in cytoplasmic signal transduction remains unexplored. Here, we identify a cytoplasmic lncRNA, LINK-A (long intergenic non-coding RNA for kinase activation), which mediates HB-EGF-triggered, EGFR:GPNMB heterodimer-dependent HIF1α phosphorylation at Tyr 565 and Ser 797 by BRK and LRRK2, respectively. These events cause HIF1α stabilization, HIF1α-p300 interaction, and activation of HIF1α transcriptional programs under normoxic conditions. Mechanistically, LINK-A facilitates the recruitment of BRK to the EGFR:GPNMB complex and BRK kinase activation. The BRK-dependent HIF1α Tyr 565 phosphorylation interferes with Pro 564 hydroxylation, leading to normoxic HIF1α stabilization. Both LINK-A expression and LINK-A-dependent signalling pathway activation correlate with triple-negative breast cancer (TNBC), promoting breast cancer glycolysis reprogramming and tumorigenesis. Our findings illustrate the magnitude and diversity of cytoplasmic lncRNAs in signal transduction and highlight the important roles of lncRNAs in cancer.

Authors
Lin, A; Li, C; Xing, Z; Hu, Q; Liang, K; Han, L; Wang, C; Hawke, DH; Wang, S; Zhang, Y; Wei, Y; Ma, G; Park, PK; Zhou, J; Zhou, Y; Hu, Z; Zhou, Y; Marks, JR; Liang, H; Hung, M-C; Lin, C; Yang, L
MLA Citation
Lin, A, Li, C, Xing, Z, Hu, Q, Liang, K, Han, L, Wang, C, Hawke, DH, Wang, S, Zhang, Y, Wei, Y, Ma, G, Park, PK, Zhou, J, Zhou, Y, Hu, Z, Zhou, Y, Marks, JR, Liang, H, Hung, M-C, Lin, C, and Yang, L. "The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer." Nature cell biology 18.2 (February 2016): 213-224.
PMID
26751287
Source
epmc
Published In
Nature Cell Biology
Volume
18
Issue
2
Publish Date
2016
Start Page
213
End Page
224
DOI
10.1038/ncb3295

Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer.

Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.

Authors
Lawrenson, K; Iversen, ES; Tyrer, J; Weber, RP; Concannon, P; Hazelett, DJ; Li, Q; Marks, JR; Berchuck, A; Lee, JM; Aben, KKH; Anton-Culver, H; Antonenkova, N; Bandera, EV; Bean, Y; Beckmann, MW; Bisogna, M; Bjorge, L; Bogdanova, N; Brinton, LA; Brooks-Wilson, A; Bruinsma, F; Butzow, R; Campbell, IG; Carty, K; Chang-Claude, J; Chenevix-Trench, G; Chen, A; Chen, Z; Cook, LS; Cramer, DW; Cunningham, JM; Cybulski, C; Plisiecka-Halasa, J; Dennis, J; Dicks, E; Doherty, JA; Dörk, T; du Bois, A et al.
MLA Citation
Lawrenson, K, Iversen, ES, Tyrer, J, Weber, RP, Concannon, P, Hazelett, DJ, Li, Q, Marks, JR, Berchuck, A, Lee, JM, Aben, KKH, Anton-Culver, H, Antonenkova, N, Bandera, EV, Bean, Y, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Chenevix-Trench, G, Chen, A, Chen, Z, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Plisiecka-Halasa, J, Dennis, J, Dicks, E, Doherty, JA, Dörk, T, and du Bois, A et al. "Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer." Carcinogenesis 36.11 (November 2015): 1341-1353.
PMID
26424751
Source
epmc
Published In
Carcinogenesis
Volume
36
Issue
11
Publish Date
2015
Start Page
1341
End Page
1353
DOI
10.1093/carcin/bgv138

Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma.

To identify angiogenic biomarkers associated with tumor angiogenesis and clinical outcome in high-grade serous ovarian cancer (HGSC).51 HGSC samples were analyzed using Affymetrix HG-U133A microarray. Microvessel density (MVD) counts were determined using CD31 and CD105. Associations between mRNA expression levels and overall survival were assessed using rank score statistic. Effect size was estimated as a hazard ratio (HR) under a proportional hazard model. The Storey q-value method was used to account for multiple testing within the false-discovery rate (FDR) framework. Publicly available databases including TCGA and GSE were used for external confirmation.Thirty-one angiogenic-related genes were significantly associated with survival (q≤0.05). Of these 31 genes, 4 were also associated with outcome in the TCGA data: AKT1 (q=0.02; TCGA p=0.01, HR=0.8), CD44 (q=0.003; TCGA p=0.05, HR=0.9), EPHB2 (q=0.01; TCGA p=0.05, HR=1.2), and ERBB2 (q=0.02; TCGA p=0.05, HR=1.2). While 5 were associated with outcome in the GSE database: FLT1 (q=0.03; GSE26712 p=0.01, HR=3.1); PF4 (q=0.02; GSE26712 p=0.01, HR=3.0); NRP1 (q=0.02; GSE26712 p<0.04, HR>1.4); COL4A3 (q=0.04; GSE26712 p=0.03, HR=1.3); and ANGPTL3 (q=0.02; GSE14764 p=0.02, HR=1.5). High AKT1 and CD44 were associated with longer survival. In contrast, high expression of EPHB2, ERBB2, FLT1; PF4, NRP1, COL4A3, and ANGPTL3 were associated with shorter survival. CD105-MVD and CD31-MVD were not significantly associated with angiogenic gene expression.Thirty-one angiogenic-related genes were associated with survival in advanced HGSC and nine of these genes were confirmed in independent publicly available databases.

Authors
Siamakpour-Reihani, S; Owzar, K; Jiang, C; Turner, T; Deng, Y; Bean, SM; Horton, JK; Berchuck, A; Marks, JR; Dewhirst, MW; Alvarez Secord, A
MLA Citation
Siamakpour-Reihani, S, Owzar, K, Jiang, C, Turner, T, Deng, Y, Bean, SM, Horton, JK, Berchuck, A, Marks, JR, Dewhirst, MW, and Alvarez Secord, A. "Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma." Gynecologic oncology 139.1 (October 2015): 23-29.
PMID
26260910
Source
epmc
Published In
Gynecologic Oncology
Volume
139
Issue
1
Publish Date
2015
Start Page
23
End Page
29
DOI
10.1016/j.ygyno.2015.08.001

Expression profiling of in vivo ductal carcinoma in situ progression models identified B cell lymphoma-9 as a molecular driver of breast cancer invasion.

There are an estimated 60,000 new cases of ductal carcinoma in situ (DCIS) each year. A lack of understanding in DCIS pathobiology has led to overtreatment of more than half of patients. We profiled the temporal molecular changes during DCIS transition to invasive ductal carcinoma (IDC) using in vivo DCIS progression models. These studies identified B cell lymphoma-9 (BCL9) as a potential molecular driver of early invasion. BCL9 is a newly found co-activator of Wnt-stimulated β-catenin-mediated transcription. BCL9 has been shown to promote progression of multiple myeloma and colon carcinoma. However BCL9 role in breast cancer had not been previously recognized.Microarray and RNA sequencing were utilized to characterize the sequential changes in mRNA expression during DCIS invasive transition. BCL9-shRNA knockdown was performed to assess the role of BCL9 in in vivo invasion, epithelial-mesenchymal transition (EMT) and canonical Wnt-signaling. Immunofluorescence of 28 patient samples was used to assess a correlation between the expression of BCL9 and biomarkers of high risk DCIS. The cancer genome atlas data were analyzed to assess the status of BCL9 gene alterations in breast cancers.Analysis of BCL9, by RNA and protein showed BCL9 up-regulation to be associated with DCIS transition to IDC. Analysis of patient DCIS revealed a significant correlation between high nuclear BCL9 and pathologic characteristics associated with DCIS recurrence: Estrogen receptor (ER) and progesterone receptor (PR) negative, high nuclear grade, and high human epidermal growth factor receptor2 (HER2). In vivo silencing of BCL9 resulted in the inhibition of DCIS invasion and reversal of EMT. Analysis of the TCGA data showed BCL9 to be altered in 26 % of breast cancers. This is a significant alteration when compared to HER2 (ERBB2) gene (19 %) and estrogen receptor (ESR1) gene (8 %). A significantly higher proportion of basal like invasive breast cancers compared to luminal breast cancers showed BCL9 amplification.BCL9 is a molecular driver of DCIS invasive progression and may predispose to the development of basal like invasive breast cancers. As such, BCL9 has the potential to serve as a biomarker of high risk DCIS and as a therapeutic target for prevention of IDC.

Authors
Elsarraj, HS; Hong, Y; Valdez, KE; Michaels, W; Hook, M; Smith, WP; Chien, J; Herschkowitz, JI; Troester, MA; Beck, M; Inciardi, M; Gatewood, J; May, L; Cusick, T; McGinness, M; Ricci, L; Fan, F; Tawfik, O; Marks, JR; Knapp, JR; Yeh, H-W; Thomas, P; Carrasco, DR; Fields, TA; Godwin, AK; Behbod, F
MLA Citation
Elsarraj, HS, Hong, Y, Valdez, KE, Michaels, W, Hook, M, Smith, WP, Chien, J, Herschkowitz, JI, Troester, MA, Beck, M, Inciardi, M, Gatewood, J, May, L, Cusick, T, McGinness, M, Ricci, L, Fan, F, Tawfik, O, Marks, JR, Knapp, JR, Yeh, H-W, Thomas, P, Carrasco, DR, Fields, TA, Godwin, AK, and Behbod, F. "Expression profiling of in vivo ductal carcinoma in situ progression models identified B cell lymphoma-9 as a molecular driver of breast cancer invasion." Breast cancer research : BCR 17 (September 17, 2015): 128-.
PMID
26384318
Source
epmc
Published In
Breast Cancer Research
Volume
17
Publish Date
2015
Start Page
128
DOI
10.1186/s13058-015-0630-z

Cancer associated macrophage-like cells as a blood-based biomarker for the screening of solid tumors

Authors
Adams, D; Alpaugh, K; Cristofanilli, M; Martin, S; Chumsri, S; Bergen, RC; Tsai, S; Edelman, M; Zhu, P; Li, S; Makarova, OV; Amstutz, PT; Tang, C-M; Marks, JR
MLA Citation
Adams, D, Alpaugh, K, Cristofanilli, M, Martin, S, Chumsri, S, Bergen, RC, Tsai, S, Edelman, M, Zhu, P, Li, S, Makarova, OV, Amstutz, PT, Tang, C-M, and Marks, JR. "Cancer associated macrophage-like cells as a blood-based biomarker for the screening of solid tumors." August 1, 2015.
Source
wos-lite
Published In
Cancer Research
Volume
75
Publish Date
2015
DOI
10.1158/1538-7445.AM2015-5165

Early detection of breast cancer using a unique tumor specific antibody

Authors
Das Roy, L; Zhou, R; Moore, LJ; Dillon, LM; Puri, R; Lyerly, K; Marks, JR; Mukherjee, P
MLA Citation
Das Roy, L, Zhou, R, Moore, LJ, Dillon, LM, Puri, R, Lyerly, K, Marks, JR, and Mukherjee, P. "Early detection of breast cancer using a unique tumor specific antibody." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Construction and analysis of the NCI-EDRN breast cancer reference set for circulating markers of disease.

Many circulating biomarkers have been reported for the diagnosis of breast cancer, but few, if any, have undergone rigorous credentialing using prospective cohorts and blinded evaluation.The NCI Early Detection Research Network (EDRN) has created a prospective, multicenter collection of plasma and serum samples from 832 subjects designed to evaluate circulating biomarkers for the detection and diagnosis of breast cancer. These samples are available to investigators who wish to evaluate their biomarkers using a set of blinded samples. The breast cancer reference set is composed of blood samples collected using a standard operating procedure at four U.S. medical centers from 2008 to 2010 from women undergoing either tissue diagnosis for breast cancer or routine screening mammography. The reference set contains samples from women with incident invasive cancer (n = 190), carcinoma in situ (n = 55), benign pathology with atypia (n = 63), benign disease with no atypia (n = 231), and women with no evidence of breast disease by screening mammography (BI-RADS 1 or 2, n = 276). Using a subset of plasma samples (n = 505) from the reference set, we analyzed 90 proteins by multiplexed immunoassays for their potential utility as diagnostic markers.We found that none of these markers is useful for distinguishing cancer from benign controls. However, elevated CA-125 does appear to be a candidate marker for estrogen receptor-negative cancers.Markers that can distinguish benign breast conditions from invasive cancer have not yet been found.Availability of prospectively collected samples should improve future validation efforts.

Authors
Marks, JR; Anderson, KS; Engstrom, P; Godwin, AK; Esserman, LJ; Longton, G; Iversen, ES; Mathew, A; Patriotis, C; Pepe, MS
MLA Citation
Marks, JR, Anderson, KS, Engstrom, P, Godwin, AK, Esserman, LJ, Longton, G, Iversen, ES, Mathew, A, Patriotis, C, and Pepe, MS. "Construction and analysis of the NCI-EDRN breast cancer reference set for circulating markers of disease." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 24.2 (February 2015): 435-441.
PMID
25471344
Source
epmc
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
24
Issue
2
Publish Date
2015
Start Page
435
End Page
441
DOI
10.1158/1055-9965.epi-14-1178

A joint analysis of metabolomics and genetics of breast cancer.

Remodeling of cellular metabolism appears to be a consequence and possibly a cause of oncogenic transformation in human cancers. Specific aspects of altered tumor metabolism may be amenable to therapeutic intervention and could be coordinated with other targeted therapies. In breast cancer, the genetic landscape has been defined most comprehensively in efforts such as The Cancer Genome Atlas (TCGA). However, little is known about how alterations of tumor metabolism correlate with this landscape.In total 25 cancers (23 fully analyzed by TCGA) and 5 normal breast specimens were analyzed by gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry, quantitating 399 identifiable metabolites.We found strong differences correlated with hormone receptor status with 18% of the metabolites elevated in estrogen receptor negative (ER-) cancers compared to estrogen receptor positive (ER+) including many glycolytic and glycogenolytic intermediates consistent with increased Warburg effects. Glutathione (GSH) pathway components were also elevated in ER- tumors consistent with an increased requirement for handling higher levels of oxidative stress. Additionally, ER- tumors had high levels of the oncometabolite 2-hydroxyglutarate (2-HG) and the immunomodulatory tryptophan metabolite kynurenine. Kynurenine levels were correlated with the expression of tryptophan-degrading enzyme (IDO1). However, high levels of 2-HG were not associated with somatic mutations or expression levels of IDH1 or IDH2. BRCA1 mRNA levels were positively associated with coenzyme A, acetyl coenzyme A, and GSH and negatively associated with multiple lipid species, supporting the regulation of ACC1 and NRF2 by BRCA1. Different driver mutations were associated with distinct patterns of specific metabolites, such as lower levels of several lipid-glycerophosphocholines in tumors with mutated TP53. A strong metabolomic signature associated with proliferation rate was also observed; the metabolites in this signature overlap broadly with metabolites that define ER status as receptor status and proliferation rate were correlated.The addition of metabolomic profiles to the public domain TCGA dataset provides an important new tool for discovery and hypothesis testing of the genetic regulation of tumor metabolism. Particular sets of metabolites may reveal insights into the metabolic dysregulation that underlie the heterogeneity of breast cancer.

Authors
Tang, X; Lin, C-C; Spasojevic, I; Iversen, ES; Chi, J-T; Marks, JR
MLA Citation
Tang, X, Lin, C-C, Spasojevic, I, Iversen, ES, Chi, J-T, and Marks, JR. "A joint analysis of metabolomics and genetics of breast cancer." Breast cancer research : BCR 16.4 (August 5, 2014): 415-.
PMID
25091696
Source
epmc
Published In
Breast Cancer Research
Volume
16
Issue
4
Publish Date
2014
Start Page
415
DOI
10.1186/s13058-014-0415-9

Refining the role of BRCA1 in combating oxidative stress.

The BRCA1 hereditary susceptibility gene has been studied in great depth, befitting its clear role in promoting basal type breast cancer and serous type ovarian (fallopian tube) cancer in women carrying germline mutations. The BRCA1 protein has long been implicated in maintaining genome integrity through DNA repair processes. However, a number of studies have demonstrated that BRCA1 is also involved in the response to oxidative stress. A recent paper by Gorrini and colleagues extends our mechanistic understanding of how BRCA1 regulates this pathway. The relative contribution of this activity in BRCA1-associated tumorigenesis and DNA damage response remains unknown.

Authors
Marks, JR
MLA Citation
Marks, JR. "Refining the role of BRCA1 in combating oxidative stress. (Published online)" Breast Cancer Res 15.6 (December 5, 2013): 320-.
PMID
24314328
Source
pubmed
Published In
Breast Cancer Research
Volume
15
Issue
6
Publish Date
2013
Start Page
320
DOI
10.1186/bcr3583

Molecular signatures of epithelial ovarian cancer: analysis of associations with tumor characteristics and epidemiologic risk factors.

BACKGROUND: Six gene expression subtypes of invasive epithelial ovarian cancer were recently defined using microarrays by Tothill and colleagues. The Cancer Genome Atlas (TCGA) project subsequently replicated these subtypes and identified a signature predictive of survival in high-grade serous (HGS) cancers. We previously validated these signatures for use in formalin-fixed paraffin-embedded tissues. The aim of the present study was to determine whether these signatures are associated with specific ovarian cancer risk factors, which would add to the evidence that they reflect the heterogeneous etiology of this disease. METHODS: We modeled signature-specific tumor characteristics and epidemiologic risk factor relationships using multiple regression and multivariate response multiple regression models in 193 patients from a case-control study of epithelial ovarian cancer. RESULTS: We observed associations between the Tothill gene expression subtype signatures and both age at diagnosis (P = 0.0008) and race (P = 0.008). Although most established epidemiologic risk factors were not associated with molecular signatures, there was an association between breast feeding (P = 0.024) and first-degree family history of breast or ovarian cancer (P = 0.034) among the 106 HGS cases. Some of the above associations were validated using gene expression microarray data from the TCGA project. Weak associations were seen with age at menarche and duration of oral contraceptive use and the TCGA survival signature. CONCLUSIONS: These data support the potential for genomic characterization to elucidate the etiologic heterogeneity of epithelial ovarian cancer. IMPACT: This study suggests that molecular signatures may augment the ability to define etiologic subtypes of epithelial ovarian cancer.

Authors
Schildkraut, JM; Iversen, ES; Akushevich, L; Whitaker, R; Bentley, RC; Berchuck, A; Marks, JR
MLA Citation
Schildkraut, JM, Iversen, ES, Akushevich, L, Whitaker, R, Bentley, RC, Berchuck, A, and Marks, JR. "Molecular signatures of epithelial ovarian cancer: analysis of associations with tumor characteristics and epidemiologic risk factors." Cancer Epidemiol Biomarkers Prev 22.10 (October 2013): 1709-1721.
PMID
23917454
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
22
Issue
10
Publish Date
2013
Start Page
1709
End Page
1721
DOI
10.1158/1055-9965.EPI-13-0192

Validation of ovarian cancer gene expression signatures for survival and subtype in formalin fixed paraffin embedded tissues.

INTRODUCTION: Gene expression signatures have been identified for epithelial ovarian cancer survival (TCGA) and intrinsic subtypes (Tothill et al.). One obstacle to clinical translation is that these signatures were developed using frozen tissue, whereas usually only formalin-fixed, paraffin embedded (FFPE) tissue is available. The aim of this study was to determine if gene expression signatures can be translated to fixed archival tissues. METHODS: RNA extracted from FFPE sections from 240 primary ovarian cancers was analyzed by DASL on Illumina BeadChip arrays. Concordance of expression at the individual gene level was assessed by comparing array data from the same cancers (30 frozen samples analyzed on Affymetrix arrays versus FFPE DASL). RESULTS: The correlation between FFPE and frozen survival signature estimates was 0.774. The TCGA signature using DASL was predictive of survival in 106 advanced stage high grade serous ovarian cancers (median survival 33 versus 60 months, estimated hazard ratio for death 2.30, P=0.0007). Similar to Tothill, we found using DASL that most high grade serous ovarian cancers (102/110, 93%) were assigned to subtypes 1, 2, 4 and 5, whereas most endometrioid, clear cell, mucinous and low grade serous cases (39/57, 68%) were assigned to subtypes 3 and 6 (P<10e-15). CONCLUSIONS: Although individual probe estimates of microarrays may be weakly correlated between FFPE and frozen samples, combinations of probes have robust ability to predict survival and subtype. This suggests that it may be possible to use these signatures for prognostic and predictive purposes as we seek to individualize the treatment of ovarian cancer.

Authors
Sfakianos, GP; Iversen, ES; Whitaker, R; Akushevich, L; Schildkraut, JM; Murphy, SK; Marks, JR; Berchuck, A
MLA Citation
Sfakianos, GP, Iversen, ES, Whitaker, R, Akushevich, L, Schildkraut, JM, Murphy, SK, Marks, JR, and Berchuck, A. "Validation of ovarian cancer gene expression signatures for survival and subtype in formalin fixed paraffin embedded tissues." Gynecol Oncol 129.1 (April 2013): 159-164.
PMID
23274563
Source
pubmed
Published In
Gynecologic Oncology
Volume
129
Issue
1
Publish Date
2013
Start Page
159
End Page
164
DOI
10.1016/j.ygyno.2012.12.030

Vitamin D receptor (VDR) polymorphisms and risk of ovarian cancer in Caucasian and African American women.

OBJECTIVE: Polymorphisms in the vitamin D receptor (VDR) gene have been shown in some studies to be associated with the risk of epithelial ovarian cancer (EOC) in Caucasian women. There are no published reports among African Americans. METHODS: Case-control data from the North Carolina Ovarian Cancer Study were analyzed using logistic regression to determine the association between seven VDR polymorphisms and EOC in both Caucasians (513 cases, 532 controls) and African Americans (74 cases, 79 controls). In a larger sample of African-Americans (125 cases, 155 controls), we assessed associations between six SNPs in proximity of rs7975232. RESULTS: African American women who carried at least one minor allele of rs7975232 were at higher risk for invasive EOC controlling for age and admixture with an odds ratio (OR) for association under the log-additive model of 2.08 (95% confidence interval (CI)=1.19, 3.63, p=0.010). No association was observed between any of the VDR variants and EOC among Caucasians. A larger sample of African Americans revealed a nearly two-fold increased risk of invasive EOC associated with rs7305032, a SNP in proximity to rs7975232 (R(2)=0.369) with a log-additive OR of 1.87 (95% CI=1.20, 2.93, p=0.006). CONCLUSIONS: This is the first report showing VDR variants associated with ovarian cancer risk in African American women. A larger study of African American women is needed to confirm these findings. These results imply that vitamin D exposure is a possible modifiable risk factor of ovarian cancer among African Americans.

Authors
Grant, DJ; Hoyo, C; Akushevich, L; Iversen, ES; Whitaker, R; Marks, J; Berchuck, A; Schildkraut, JM
MLA Citation
Grant, DJ, Hoyo, C, Akushevich, L, Iversen, ES, Whitaker, R, Marks, J, Berchuck, A, and Schildkraut, JM. "Vitamin D receptor (VDR) polymorphisms and risk of ovarian cancer in Caucasian and African American women." Gynecol Oncol 129.1 (April 2013): 173-178.
PMID
23262379
Source
pubmed
Published In
Gynecologic Oncology
Volume
129
Issue
1
Publish Date
2013
Start Page
173
End Page
178
DOI
10.1016/j.ygyno.2012.12.027

Oxidatively modified proteins as plasma biomarkers in breast cancer

BACKGROUND: Post-translational protein modifications (PTMs) are increased in breast tumors. OBJECTIVE: We explored whether PTMs on proteins secreted by the breast could be detected in plasma and potentially used for the early detection of breast cancer. METHODS: We used a custom ELISA microarray platform to measure 4-hydroxynonenal (HNE), glutathione (GSH), nitrotyrosine and halotyrosine adducts in 27 secreted proteins, for a total of 108 candidate biomarkers. Two independent sets of human plasma samples were measured, for a total of 160 samples. The results were analyzed for consistent cancer-associated changes across the two sample sets. Plasma samples for both cases and benign controls were collected at the time of tissue diagnosis after referral from a positive screen (such as mammography). The results from both studies were evaluated using ANOVA and t-tests or receiver operator curves (ROC). RESULTS: Levels of GSH-modified ceruloplasmin and HNE-modified PDGF were significantly altered in plasma samples from cancer patients relative to benign controls. Healthy controls, which were only included in the first set of samples, were similar to the benign controls for both of these markers. A combination of three glutathionylated proteins produced the best area under the ROC curve, with a value of 76%. CONCLUSIONS: Specific PTMs in individual proteins may be useful for distinguishing between women with breast cancer and those with benign breast disease. These oxidative changes in plasma proteins may reflect redox changes in breast cancer. Additional studies on oxidative modifications in individual proteins are warranted. © 2013 - IOS Press and the authors. All rights reserved.

Authors
Jin, H; Daly, DS; Marks, JR; Zangar, RC
MLA Citation
Jin, H, Daly, DS, Marks, JR, and Zangar, RC. "Oxidatively modified proteins as plasma biomarkers in breast cancer." Cancer Biomarkers 13.3 (2013): 193-200.
PMID
23912491
Source
scival
Published In
Cancer biomarkers : section A of Disease markers
Volume
13
Issue
3
Publish Date
2013
Start Page
193
End Page
200
DOI
10.3233/CBM-130349

Comprehensive molecular portraits of human breast tumours

Authors
Koboldt, DC; Fulton, RS; McLellan, MD; Schmidt, H; Kalicki-Veizer, J; McMichael, JF; Fulton, LL; Dooling, DJ; Ding, L; Mardis, ER; Wilson, RK; Ally, A; Balasundaram, M; Butterfield, YSN; Carlsen, R; Carter, C; Chu, A; Chuah, E; Chun, H-JE; Coope, RJN; Dhalla, N; Guin, R; Hirst, C; Hirst, M; Holt, RA; Lee, D; Li, HI; Mayo, M; Moore, RA; Mungall, AJ; Pleasance, E; Robertson, AG; Schein, JE; Shafiei, A; Sipahimalani, P; Slobodan, JR; Stoll, D; Tam, A; Thiessen, N; Varhol, RJ; Wye, N; Zeng, T et al.
MLA Citation
Koboldt, DC, Fulton, RS, McLellan, MD, Schmidt, H, Kalicki-Veizer, J, McMichael, JF, Fulton, LL, Dooling, DJ, Ding, L, Mardis, ER, Wilson, RK, Ally, A, Balasundaram, M, Butterfield, YSN, Carlsen, R, Carter, C, Chu, A, Chuah, E, Chun, H-JE, Coope, RJN, Dhalla, N, Guin, R, Hirst, C, Hirst, M, Holt, RA, Lee, D, Li, HI, Mayo, M, Moore, RA, Mungall, AJ, Pleasance, E, Robertson, AG, Schein, JE, Shafiei, A, Sipahimalani, P, Slobodan, JR, Stoll, D, Tam, A, Thiessen, N, Varhol, RJ, Wye, N, and Zeng, T et al. "Comprehensive molecular portraits of human breast tumours." NATURE 490.7418 (October 4, 2012): 61-70.
Source
wos-lite
Published In
Nature
Volume
490
Issue
7418
Publish Date
2012
Start Page
61
End Page
70
DOI
10.1038/nature11412

Glutamine synthetase is a genetic determinant of cell-type specific glutamine independence in breast epithelia

Authors
Kung, H-N; Marks, JR; Chi, J-TA
MLA Citation
Kung, H-N, Marks, JR, and Chi, J-TA. "Glutamine synthetase is a genetic determinant of cell-type specific glutamine independence in breast epithelia." April 15, 2012.
Source
wos-lite
Published In
Cancer Research
Volume
72
Publish Date
2012
DOI
10.1158/1538-7445.AM2012-3210

Loss of ARID1A-associated protein expression is a frequent event in clear cell and endometrioid ovarian cancers.

BACKGROUND: Inactivating somatic mutations in the ARID1A gene are described in a significant fraction of clear cell and endometrioid ovarian cancers leading to loss of the corresponding protein (BAF250a). Expression of BAF250a was examined in clear cell and endometrioid cancers accrued as part of the North Carolina Ovarian Cancer Study, a population-based case-control study, to determine whether loss of expression is associated with clinical and epidemiological features. METHODS: Immunostaining for BAF250a was performed using 212 clear cell and endometrioid ovarian cancers. Associations between loss of BAF250a and clinical and epidemiological features were examined. Variables were analyzed by logistic regression. RESULTS: Loss of BAF250a expression was noted in 96 (45%) of 212 cancers: 34 (41%) of 82 clear cell cases and 62 (48%) of 130 endometrioid cases. There was no relationship between the loss of BAF250a and stage, grade, survival, or epidemiological variables. CONCLUSIONS: These data confirm that loss of the ARID1A-encoded protein BAF250a is a frequent event in the genesis of clear cell and endometrioid ovarian cancers. Loss of BAF250a was not associated with clinical or epidemiologic characteristics. One explanation for these findings is that inactivation of the chromatin remodeling pathway may be a requisite event in the development of these cancers.

Authors
Lowery, WJ; Schildkraut, JM; Akushevich, L; Bentley, R; Marks, JR; Huntsman, D; Berchuck, A
MLA Citation
Lowery, WJ, Schildkraut, JM, Akushevich, L, Bentley, R, Marks, JR, Huntsman, D, and Berchuck, A. "Loss of ARID1A-associated protein expression is a frequent event in clear cell and endometrioid ovarian cancers." Int J Gynecol Cancer 22.1 (January 2012): 9-14.
PMID
22193641
Source
pubmed
Published In
International Journal of Gynecological Cancer
Volume
22
Issue
1
Publish Date
2012
Start Page
9
End Page
14
DOI
10.1097/IGC.0b013e318231f140

An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer (Journal of Clinical Oncology (2007) 25 (517-525))

Authors
Dressman, HK; Berchuck, A; Chan, G; Zhai, J; Bild, A; Sayer, R; Cragun, J; Clarke, J; Whitaker, RS; Li, L; Gray, J; Marks, J; Ginsburg, GS; Potti, A; West, M; Nevins, JR; Lancaster, JM
MLA Citation
Dressman, HK, Berchuck, A, Chan, G, Zhai, J, Bild, A, Sayer, R, Cragun, J, Clarke, J, Whitaker, RS, Li, L, Gray, J, Marks, J, Ginsburg, GS, Potti, A, West, M, Nevins, JR, and Lancaster, JM. "An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer (Journal of Clinical Oncology (2007) 25 (517-525))." Journal of Clinical Oncology 30.6 (2012): 678--.
Source
scival
Published In
Journal of Clinical Oncology
Volume
30
Issue
6
Publish Date
2012
Start Page
678-
DOI
10.1200/JCO.2012.42.0331

Glutamine synthetase is a genetic determinant of cell type-specific glutamine independence in breast epithelia.

Although significant variations in the metabolic profiles exist among different cells, little is understood in terms of genetic regulations of such cell type-specific metabolic phenotypes and nutrient requirements. While many cancer cells depend on exogenous glutamine for survival to justify the therapeutic targeting of glutamine metabolism, the mechanisms of glutamine dependence and likely response and resistance of such glutamine-targeting strategies among cancers are largely unknown. In this study, we have found a systematic variation in the glutamine dependence among breast tumor subtypes associated with mammary differentiation: basal- but not luminal-type breast cells are more glutamine-dependent and may be susceptible to glutamine-targeting therapeutics. Glutamine independence of luminal-type cells is associated mechanistically with lineage-specific expression of glutamine synthetase (GS). Luminal cells can also rescue basal cells in co-culture without glutamine, indicating a potential for glutamine symbiosis within breast ducts. The luminal-specific expression of GS is directly induced by GATA3 and represses glutaminase expression. Such distinct glutamine dependency and metabolic symbiosis is coupled with the acquisition of the GS and glutamine independence during the mammary differentiation program. Understanding the genetic circuitry governing distinct metabolic patterns is relevant to many symbiotic relationships among different cells and organisms. In addition, the ability of GS to predict patterns of glutamine metabolism and dependency among tumors is also crucial in the rational design and application of glutamine and other metabolic pathway targeted therapies.

Authors
Kung, H-N; Marks, JR; Chi, J-T
MLA Citation
Kung, H-N, Marks, JR, and Chi, J-T. "Glutamine synthetase is a genetic determinant of cell type-specific glutamine independence in breast epithelia." PLoS Genet 7.8 (August 2011): e1002229-.
PMID
21852960
Source
pubmed
Published In
PLoS genetics
Volume
7
Issue
8
Publish Date
2011
Start Page
e1002229
DOI
10.1371/journal.pgen.1002229

The turnover of estrogen receptor α by the selective estrogen receptor degrader (SERD) fulvestrant is a saturable process that is not required for antagonist efficacy.

It has become apparent of late that even in tamoxifen and/or aromatase resistant breast cancers, ERα remains a bona fide therapeutic target. Not surprisingly, therefore, there has been considerable interest in developing Selective ER Degraders (SERDs), compounds that target the receptor for degradation. Currently, ICI 182,780 (ICI, fulvestrant) is the only SERD approved for the treatment of breast cancer. However, the poor pharmaceutical properties of this injectable drug and its lack of superiority over second line aromatase inhibitors in late stage breast cancer have negatively impacted its clinical use. These findings have provided the impetus to develop second generation, orally bioavailable SERDs with which quantitative turnover of ERα in tumors can be achieved. Interestingly however, the contribution of SERD activity to fulvestrant efficacy is unclear, making it difficult to define the characteristics desired of the next generation of ER antagonists. It is of significance therefore, that we have determined that the antagonist activity of ICI and its ability to induce ERα degradation are not coupled processes. Specifically, our results indicate that it is the ability of ICI to interact with ERα and to (a) competitively displace estradiol and (b) induce a conformational change in ER incompatible with transcriptional activation that are likely to be the most important pharmacological characteristics of this drug. Collectively, these data argue for a renewed emphasis on the development of high affinity, orally bioavailable pure antagonists and suggest that SERD activity though proven effective may not be required for ERα antagonism in breast cancer.

Authors
Wardell, SE; Marks, JR; McDonnell, DP
MLA Citation
Wardell, SE, Marks, JR, and McDonnell, DP. "The turnover of estrogen receptor α by the selective estrogen receptor degrader (SERD) fulvestrant is a saturable process that is not required for antagonist efficacy." Biochem Pharmacol 82.2 (July 15, 2011): 122-130.
PMID
21501600
Source
pubmed
Published In
Biochemical Pharmacology
Volume
82
Issue
2
Publish Date
2011
Start Page
122
End Page
130
DOI
10.1016/j.bcp.2011.03.031

Analysis of tumor environmental response and oncogenic pathway activation identifies distinct basal and luminal features in HER2-related breast tumor subtypes.

INTRODUCTION: Breast cancer heterogeneity occurs as a consequence of the dysregulation of numerous oncogenic pathways as well as many non-genetic factors, including tumor microenvironmental stresses such as hypoxia, lactic acidosis, and glucose deprivation. Although the importance of these non-genetic factors is well recognized, it is not clear how to integrate these factors within the genetic framework of cancer as the next logical step in understanding tumor heterogeneity. METHODS: We report here the development of a series of gene expression signatures to measure the influences of microenvironmental stresses. The pathway activities of hypoxia, lactic acidosis, acidosis and glucose deprivation were investigated in a collection of 1,143 breast tumors, which have been separated into 17 breast tumor subgroups defined by their distinct patterns of oncogenic pathways. A validation dataset comprised of 547 breast tumors was also used to confirm the major findings, and representative breast cancer cell lines were utilized to validate in silico results and mechanistic studies. RESULTS: Through the integrative pathway analysis of microenvironmental stresses and oncogenic events in breast tumors, we identified many known and novel correlations between these two sources of tumor heterogeneity. Focusing on differences between two human epidermal growth factor receptor 2 (HER2)-related subgroups, previously identified based on patterns of oncogenic pathway activity, we determined that these subgroups differ with regards to tumor microenvironmental signatures, including hypoxia. We further demonstrate that each of these subgroups have features consistent with basal and luminal breast tumors including patterns of oncogenic signaling pathways, expression of subtype specific genes, and cellular mechanisms that regulate the hypoxia response. Importantly, we also demonstrate that the correlated pattern of hypoxia-related gene expression and basal-associated gene expression are consistent across HER2-related tumors whether we analyze the tumors as a function of our pathway-based classification scheme, using the intrinsic gene list (ERBB2+), or based on HER2 IHC status. Our results demonstrate a cell lineage-specific phenomenon in which basal-like tumors, HER2-related tumors with high hypoxia, as well as normal basal epithelial cells express increased mRNA levels of HIF-1α compared to luminal types and silencing of HIF-1α results in decreased expression of hypoxia-induced genes. CONCLUSIONS: This study demonstrates differences in microenvironmental conditions in HER2-related subgroups defined by distinct oncogenic pathway activities, and provides a mechanistic explanation for differences in the observed hypoxia response between these subgroups. Collectively, these data demonstrate the potential of a pathway-based classification strategy as a framework to integrate genetic and non-genetic factors to investigate the basis of tumor heterogeneity.

Authors
Gatza, ML; Kung, H-N; Blackwell, KL; Dewhirst, MW; Marks, JR; Chi, J-T
MLA Citation
Gatza, ML, Kung, H-N, Blackwell, KL, Dewhirst, MW, Marks, JR, and Chi, J-T. "Analysis of tumor environmental response and oncogenic pathway activation identifies distinct basal and luminal features in HER2-related breast tumor subtypes. (Published online)" Breast Cancer Res 13.3 (June 7, 2011): R62-.
PMID
21672245
Source
pubmed
Published In
Breast Cancer Research
Volume
13
Issue
3
Publish Date
2011
Start Page
R62
DOI
10.1186/bcr2899

Regulator of G protein signaling 5 is highly expressed in parathyroid tumors and inhibits signaling by the calcium-sensing receptor.

The molecular mechanisms responsible for aberrant calcium signaling in parathyroid disease are poorly understood. The loss of appropriate calcium-responsive modulation of PTH secretion observed in parathyroid disease is commonly attributed to decreased expression of the calcium-sensing receptor (CaSR), a G protein-coupled receptor. However, CaSR expression is highly variable in parathyroid adenomas, and the lack of correlation between CaSR abundance and calcium-responsive PTH kinetics indicates that mechanisms independent of CaSR expression may contribute to aberrant calcium sensing in parathyroid disease. To gain a better understanding of parathyroid tumors and the molecular determinants that drive parathyroid adenoma development, we performed gene expression profiling on a panel of 64 normal and neoplastic parathyroid tissues. The microarray data revealed high-level expression of genes known to be involved in parathyroid biology (PTH, VDR, CGA, CaSR, and GCM2). Moreover, our screen identified regulator of G protein signaling 5 (RGS5) as a candidate inhibitor of CaSR signaling. We confirmed RGS5 to be highly expressed in parathyroid adenomas relative to matched-pair normal glands. Transient expression of RGS5 in cells stably expressing CaSR resulted in dose-dependent abrogation of calcium-stimulated inositol trisphosphate production and ERK1/2 phosphorylation. Furthermore, we found that RGS5-nullizygous mice display reduced plasma PTH levels, an outcome consistent with attenuated opposition to CaSR activity. Collectively, these data suggest that RGS5 can act as a physiological regulator of calcium sensing by CaSR in the parathyroid gland. The abnormally elevated expression of RGS5 observed in parathyroid adenomas could thus represent a novel mechanism of CaSR desensitization in patients with primary hyperparathyroidism.

Authors
Koh, J; Dar, M; Untch, BR; Dixit, D; Shi, Y; Yang, Z; Adam, MA; Dressman, H; Wang, X; Gesty-Palmer, D; Marks, JR; Spurney, R; Druey, KM; Olson, JA
MLA Citation
Koh, J, Dar, M, Untch, BR, Dixit, D, Shi, Y, Yang, Z, Adam, MA, Dressman, H, Wang, X, Gesty-Palmer, D, Marks, JR, Spurney, R, Druey, KM, and Olson, JA. "Regulator of G protein signaling 5 is highly expressed in parathyroid tumors and inhibits signaling by the calcium-sensing receptor." Mol Endocrinol 25.5 (May 2011): 867-876.
PMID
21393447
Source
pubmed
Published In
Molecular endocrinology (Baltimore, Md.)
Volume
25
Issue
5
Publish Date
2011
Start Page
867
End Page
876
DOI
10.1210/me.2010-0277

Abstract 3182: PTM ELISA microarray for breast cancer biomarker discovery

Authors
Jin, H; Daly, DS; Tan, R; White, AM; Marks, JR; Zangar, RC
MLA Citation
Jin, H, Daly, DS, Tan, R, White, AM, Marks, JR, and Zangar, RC. "Abstract 3182: PTM ELISA microarray for breast cancer biomarker discovery." Cancer Research 71.8 Supplement (April 15, 2011): 3182-3182.
Source
crossref
Published In
Cancer Research
Volume
71
Issue
8 Supplement
Publish Date
2011
Start Page
3182
End Page
3182
DOI
10.1158/1538-7445.AM2011-3182

Development of an ovarian cancer screening decision model that incorporates disease heterogeneity: implications for potential mortality reduction.

BACKGROUND: Pathologic and genetic data suggest that epithelial ovarian cancer may consist of indolent and aggressive phenotypes. The objective of the current study was to estimate the impact of a 2-phenotype paradigm of epithelial ovarian cancer on the mortality reduction achievable using available screening technologies. METHODS: The authors modified a Markov model of ovarian cancer natural history (the 1-phenotype model) to incorporate aggressive and indolent phenotypes (the 2-phenotype model) based on histopathologic criteria. Stage distribution, incidence, and mortality were calibrated to data from the Surveillance, Epidemiology, and End Results Program of the US National Cancer Institute. For validation, a Monte Carlo microsimulation (1000,000 events) of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) multimodality prevalence screen was performed. Mortality reduction and positive predictive value (PPV) were estimated for annual screening. RESULTS: In validation against UKCTOCS data, the model-predicted percentage of screen-detected cancers diagnosed at stage I and II was 41% compared with 47% (UKCTOCS data), and the model-predicted PPV of screening was 27% compared with 35% (UKCTOCS data). The model-estimated PPV of a strategy of annual population-based screening in the United States at ages 50 to 85 years was 14%. The mortality reduction using annual postmenopausal screening was 14.7% (1-phenotype model) and 10.9% (2-phenotype model). Mortality reduction was lower with the 2-phenotype model than with the 1-phenotype model regardless of screening frequency or test sensitivity; 68% of cancer deaths are accounted for by the aggressive phenotype. CONCLUSIONS: The current analysis suggested that reductions in ovarian cancer mortality using available screening technologies on an annual basis are likely to be modest. A model that incorporated 2 clinical phenotypes of ovarian carcinoma into its natural history predicted an even smaller potential reduction in mortality because of the more frequent diagnosis of indolent cancers at early stages.

Authors
Havrilesky, LJ; Sanders, GD; Kulasingam, S; Chino, JP; Berchuck, A; Marks, JR; Myers, ER
MLA Citation
Havrilesky, LJ, Sanders, GD, Kulasingam, S, Chino, JP, Berchuck, A, Marks, JR, and Myers, ER. "Development of an ovarian cancer screening decision model that incorporates disease heterogeneity: implications for potential mortality reduction." Cancer 117.3 (February 1, 2011): 545-553.
PMID
21254049
Source
pubmed
Published In
Cancer
Volume
117
Issue
3
Publish Date
2011
Start Page
545
End Page
553
DOI
10.1002/cncr.25624

Individual responses to chemotherapy-induced oxidative stress.

Differences in redox homeostatic control between cancer patients may underlie predisposition to drug resistance and toxicities. To evaluate interindividual differences in redox response among newly diagnosed breast cancer patients undergoing standard chemotherapy, urine samples were collected before (T0), and at 1 (T1) and 24 h (T24) after chemotherapy administration. Oxidative status was assessed by urinary levels of allantoin and four F2-isoprostanes, quantified by LC-MS/MS. In all subjects, biomarker levels increased at T1 and returned to baseline at T24. Analyzing individual responses, two patterns were revealed: 10 subjects showed uniform increases of biomarker levels at T1 ("increase" pattern) and 8 subjects showed mixed (increase/unchanged/decrease) responses for different biomarkers ("mixed" pattern). The increase-pattern group had lower pre-treatment (T0) levels of the biomarkers and showed a sharp increase at T1 (64-141%) with a subsequent decrease at T24. The mixed-pattern group had higher pre-treatment biomarker levels and showed no change in biomarkers either at T1 or at T24. These findings indicate that there may be at least two distinct redox phenotypes with different homeostatic mechanisms balancing oxidative stress in humans. Recognizing redox phenotypes in human populations may lead to more precise assessment of health risks and benefits associated with individual redox make-up, and may also help to identify cancer patients who are especially susceptible to drug resistance and/or drug toxicity.

Authors
Il'yasova, D; Kennedy, K; Spasojevic, I; Wang, F; Tolun, AA; Base, K; Young, SP; Kelly Marcom, P; Marks, J; Millington, DS; Dewhirst, MW
MLA Citation
Il'yasova, D, Kennedy, K, Spasojevic, I, Wang, F, Tolun, AA, Base, K, Young, SP, Kelly Marcom, P, Marks, J, Millington, DS, and Dewhirst, MW. "Individual responses to chemotherapy-induced oxidative stress." Breast Cancer Res Treat 125.2 (January 2011): 583-589.
PMID
20830514
Source
pubmed
Published In
Breast Cancer Research and Treatment
Volume
125
Issue
2
Publish Date
2011
Start Page
583
End Page
589
DOI
10.1007/s10549-010-1158-7

Retraction: Genomic signatures to guide the use of chemotherapeutics.

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, RF, Chan, G, Sayer, R, Cragun, J, Cottrill, H, Kelley, MJ, Petersen, R, Harpole, D, Marks, J, Berchuck, A, Ginsburg, GS, Febbo, P, Lancaster, J, and Nevins, JR. "Retraction: Genomic signatures to guide the use of chemotherapeutics." Nat Med 17.1 (January 2011): 135-.
PMID
21217686
Source
pubmed
Published In
Nature Medicine
Volume
17
Issue
1
Publish Date
2011
Start Page
135
DOI
10.1038/nm0111-135

Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature Medicine (2006) 12 (1294-1300))

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, RF, Chan, G, Sayer, R, Cragun, J, Cottrill, H, Kelley, MJ, Petersen, R, Harpole, D, Marks, J, Berchuck, A, Ginsburg, GS, Febbo, P, Lancaster, J, and Nevins, JR. "Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature Medicine (2006) 12 (1294-1300))." Nature Medicine 17.1 (2011): 135--.
Source
scival
Published In
Nature Medicine
Volume
17
Issue
1
Publish Date
2011
Start Page
135-
DOI
10.1038/nm0111-135

Genome-wide methylation analysis identifies genes specific to breast cancer hormone receptor status and risk of recurrence

To better understand the biology of hormone receptor-positive and -negative breast cancer and to identify methylated gene markers of disease progression, we carried out a genome-wide methylation array analysis on 103 primary invasive breast cancers and 21 normal breast samples, using the Illumina Infinium HumanMethylation27 array that queried 27,578 CpG loci. Estrogen and/or progesterone receptor-positive tumors displayed more hypermethylated loci than estrogen receptor (ER)-negative tumors. However, the hypermethylated loci in ER-negative tumors were clustered closer to the transcriptional start site compared with ER-positive tumors. An ER-classifier set of CpG loci was identified, which independently partitioned primary tumors into ER subtypes. A total of 40 (32 novel and 8 previously known) CpG loci showed differential methylation specific to either ER-positive or ER-negative tumors. Each of the 40 ER subtype-specific loci was validated in silico, using an independent, publicly available methylome dataset from the Cancer Genome Atlas. In addition, we identified 100 methylated CpG loci that were significantly associated with disease progression; the majority of these loci were informative particularly in ER-negative breast cancer. Overall, the set was highly enriched in homeobox containing genes. This pilot study shows the robustness of the breast cancer methylome and illustrates its potential to stratify and reveal biological differences between ER subtypes of breast cancer. Furthermore, it defines candidate ER-specific markers and identifies potential markers predictive of outcome within ER subgroups. ©2011 AACR.

Authors
Fackler, MJ; Umbricht, CB; Williams, D; Argani, P; Cruz, L-A; Merino, VF; Teo, WW; Zhang, Z; Huang, P; Visvananthan, K; Marks, J; Ethier, S; Gray, JW; Wolff, AC; Cope, LM; Sukumar, S
MLA Citation
Fackler, MJ, Umbricht, CB, Williams, D, Argani, P, Cruz, L-A, Merino, VF, Teo, WW, Zhang, Z, Huang, P, Visvananthan, K, Marks, J, Ethier, S, Gray, JW, Wolff, AC, Cope, LM, and Sukumar, S. "Genome-wide methylation analysis identifies genes specific to breast cancer hormone receptor status and risk of recurrence." Cancer Research 71.19 (2011): 6195-6207.
PMID
21825015
Source
scival
Published In
Cancer Research
Volume
71
Issue
19
Publish Date
2011
Start Page
6195
End Page
6207
DOI
10.1158/0008-5472.CAN-11-1630

Plasma biomarker profiles differ depending on breast cancer subtype but RANTES is consistently increased

Background: Current biomarkers for breast cancer have little potential for detection. We determined whether breast cancer subtypes influence circulating protein biomarkers. Methods: A sandwich ELISA microarray platform was used to evaluate 23 candidate biomarkers in plasma samples that were obtained from subjects with either benign breast disease or invasive breast cancer. All plasma samples were collected at the time of biopsy, after a referral due to a suspicious screen (e.g., mammography). Cancer samples were evaluated on the basis of breast cancer subtypes, as defined by the HER2 and estrogen receptor statuses. Results: Ten proteins were statistically altered in at least one breast cancer subtype, including four epidermal growth factor receptor ligands, two matrix metalloproteases, two cytokines, and two angiogenic factors. Only one cytokine, RANTES, was significantly increased (P < 0.01 for each analysis) in all four subtypes, with areas under the curve (AUC) for receiver operating characteristic values that ranged from 0.76 to 0.82, depending on cancer subtype. The best AUC values were observed for analyses that combined data from multiple biomarkers, with values ranging from 0.70 to 0.99, depending on the cancer subtype. Although the results for RANTES are consistent with previous publications, the multi-assay results need to be validated in independent sample sets. Conclusions: Different breast cancer subtypes produce distinct biomarker profiles, and circulating protein biomarkers have potential to differentiate between true- and false-positive screens for breast cancer. Impact: Subtype-specific biomarker panels may be useful for detecting breast cancer or as an adjunct assay to improve the accuracy of current screening methods. ©2011 AACR.

Authors
Gonzalez, RM; Daly, DS; Tan, R; Marks, JR; Zangar, RC
MLA Citation
Gonzalez, RM, Daly, DS, Tan, R, Marks, JR, and Zangar, RC. "Plasma biomarker profiles differ depending on breast cancer subtype but RANTES is consistently increased." Cancer Epidemiology Biomarkers and Prevention 20.7 (2011): 1543-1551.
PMID
21586622
Source
scival
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
20
Issue
7
Publish Date
2011
Start Page
1543
End Page
1551
DOI
10.1158/1055-9965.EPI-10-1248

Methylation patterns in cell-free plasma DNA reflect removal of the primary tumor and drug treatment of breast cancer patients

Abnormal DNA methylation is a feature of most types of cancer, which is reflected in cell-free circulating DNA in plasma. It is, however, unknown whether surgical removal of the tumor and subsequent therapy induces changes in plasma DNA methylation, which can be used to monitor treatment. In this pilot study, methylation in cell-free plasma DNA of 20 breast cancer patients was determined by the previously developed MethDet-56 technique. Samples at three time points were analyzed-before surgery (baseline), after surgery (to evaluate the effects of resection) and after surgery on tamoxifen therapy (to determine the effects of treatment). Methylation patterns of healthy controls were used as a reference for all comparisons. Seven promoters were differentially methylated (p < 0.05) in at least one comparison; three changed after surgery; another one changed after beginning of tamoxifen treatment; and four were differentially methylated in baseline versus combined treatment samples. Increased methylation of PR PROX, MDGI, PAX 5 and RARβ2 at baseline (presurgery) diminished toward the healthy controls with the lowest methylation in the combined treatment group. Surgery alone decreased methylation in PAX 5 and RARβ2, whereas tamoxifen treatment changed methylation only in the B promoter of ESR1. Methylation patterns in cell-free plasma DNA change after surgery and tamoxifen treatment, most significantly-after combined treatment. The baseline (presurgery) patterns become similar to those of healthy controls, suggesting that methylation patterns in cell-free plasma DNA may be used to monitor treatment. Copyright © 2010 UICC.

Authors
Liggett, TE; Melnikov, AA; Marks, JR; Levenson, VV
MLA Citation
Liggett, TE, Melnikov, AA, Marks, JR, and Levenson, VV. "Methylation patterns in cell-free plasma DNA reflect removal of the primary tumor and drug treatment of breast cancer patients." International Journal of Cancer 128.2 (2011): 492-499.
PMID
20473856
Source
scival
Published In
International Journal of Cancer
Volume
128
Issue
2
Publish Date
2011
Start Page
492
End Page
499
DOI
10.1002/ijc.25363

Protein microarray signature of autoantibody biomarkers for the early detection of breast cancer

Cancer patients spontaneously generate autoantibodies (AAb) to tumor-derived proteins. To detect AAb, we have probed novel high-density custom protein microarrays (NAPPA) expressing 4988 candidate tumor antigens with sera from patients with early stage breast cancer (IBC), and bound IgG was measured. We used a three-phase serial screening approach. First, a prescreen was performed to eliminate uninformative antigens. Sera from stage I-III IBC (n = 53) and healthy women (n = 53) were screened for AAb to all 4988 protein antigens. Antigens were selected if the 95th percentile of signal of cases and controls were significantly different (p < 0.05) and if the number of cases with signals above the 95th percentile of controls was significant (p < 0.05). These 761 antigens were screened using an independent set of IBC sera (n = 51) and sera from women with benign breast disease (BBD) (n = 39). From these, 119 antigens had a partial area under the ROC curve (p < 0.05), with sensitivities ranging from 9-40% at >91% specificity. Twenty-eight of these antigens were confirmed using an independent serum cohort (n = 51 cases/38 controls, p < 0.05). Using all 28 AAb, a classifier was identified with a sensitivity of 80.8% and a specificity of 61.6% (AUC = 0.756). These are potential biomarkers for the early detection of breast cancer. © 2011 American Chemical Society.

Authors
Anderson, KS; Sibani, S; Wallstrom, G; Mendoza, EA; Raphael, J; Hainsworth, E; Montor, WR; Wong, J; Park, JG; Lokko, N; Logvinenko, T; Ramachandran, N; Godwin, AK; Marks, J; Engstrom, P; LaBaer, J
MLA Citation
Anderson, KS, Sibani, S, Wallstrom, G, Mendoza, EA, Raphael, J, Hainsworth, E, Montor, WR, Wong, J, Park, JG, Lokko, N, Logvinenko, T, Ramachandran, N, Godwin, AK, Marks, J, Engstrom, P, and LaBaer, J. "Protein microarray signature of autoantibody biomarkers for the early detection of breast cancer." Journal of Proteome Research 10.1 (2011): 85-96.
PMID
20977275
Source
scival
Published In
Journal of Proteome Research
Volume
10
Issue
1
Publish Date
2011
Start Page
85
End Page
96
DOI
10.1021/pr100686b

Evaluation of established breast cancer risk factors as modifiers of BRCA1 or BRCA2: a multi-center case-only analysis.

The incomplete penetrance of mutations in BRCA1 and BRCA2 suggests that some combination of environmental and genetic factors modifies the risk of breast cancer in mutation carriers. This study sought to identify possible interactions between established breast cancer risk factors and BRCA1 or BRCA2 mutations using a case-only study design. Breast cancer cases that had been tested for BRCA1 and BRCA2 mutations were identified from 11 collaborating centers. Comparisons of reproductive and lifestyle risk factors were made between women with breast cancer who were positive for BRCA1 mutations (n = 283), BRCA2 mutations (n = 204), or negative for both BRCA1 and BRCA2 mutations (n = 894). Interaction risk ratios (IRRs) were calculated using multinominal logistic regression models. Compared with non-carriers, statistically significant IRRs were observed for later age at menarche among BRCA2 mutation carriers, for a greater number of pregnancies among both BRCA1 and BRCA2 mutation carriers, and for alcohol use among BRCA1 mutation carriers. Our data suggest that the risk for breast cancer among BRCA1 or BRCA2 carriers may be modified by reproductive characteristics and alcohol use. However, our results should be interpreted cautiously given the overall inconsistency in the epidemiologic literature on modifiers of BRCA1 and BRCA2.

Authors
Moorman, PG; Iversen, ES; Marcom, PK; Marks, JR; Wang, F; Kathleen Cuningham Consortium for Research into Familial Breast Cancer, ; Lee, E; Ursin, G; Rebbeck, TR; Domchek, SM; Arun, B; Susswein, L; Isaacs, C; Garber, JE; Visvanathan, K; Griffin, CA; Sutphen, R; Brzosowicz, J; Gruber, S; Finkelstein, DM; Schildkraut, JM
MLA Citation
Moorman, PG, Iversen, ES, Marcom, PK, Marks, JR, Wang, F, Kathleen Cuningham Consortium for Research into Familial Breast Cancer, , Lee, E, Ursin, G, Rebbeck, TR, Domchek, SM, Arun, B, Susswein, L, Isaacs, C, Garber, JE, Visvanathan, K, Griffin, CA, Sutphen, R, Brzosowicz, J, Gruber, S, Finkelstein, DM, and Schildkraut, JM. "Evaluation of established breast cancer risk factors as modifiers of BRCA1 or BRCA2: a multi-center case-only analysis." Breast Cancer Res Treat 124.2 (November 2010): 441-451.
PMID
20309627
Source
pubmed
Published In
Breast Cancer Research and Treatment
Volume
124
Issue
2
Publish Date
2010
Start Page
441
End Page
451
DOI
10.1007/s10549-010-0842-y

Severe obesity is associated with symptomatic presentation, higher parathyroid hormone levels, and increased gland weight in primary hyperparathyroidism.

CONTEXT: A relationship between primary hyperparathyroidism (PHPT) and obesity has been observed but is incompletely understood. Furthermore, obesity has been associated with vitamin D deficiency, suggesting that the three conditions may be linked. OBJECTIVE: We hypothesized that PHPT in morbidly obese patients is more severe and that the difference may be explained by vitamin D deficiency. DESIGN AND SETTING, PARTICIPANTS, AND OUTCOME MEASURES: Records of 196 patients with surgically treated PHPT and known body mass index (BMI) were examined. Patients were stratified into three BMI groups: group I (nonobese), BMI < 25 kg/m(2) (n = 54); group II (non-severely obese), BMI 25-34 kg/m(2) (n = 102); and group III (severely obese), BMI 35 kg/m(2) or greater (n = 40). RESULTS: Preoperative PTH levels were higher in group ΙΙΙ compared with group Ι (181 ± 153 vs. 140 ± 80 pg/ml, p = 0.04). Group III patients had larger tumors on average compared with group I (1.8 ± 1.5 vs. 1.04 ± 1.5 g, P = 0.0002). In group III, BMI positively correlated with parathyroid tumor weight (r = 0.5, P = 0.002). Postoperative PTH was higher in group III compared with group Ι (61 ± 41 vs. 44 ± 28 pg/ml, P = 0.02). There was higher frequency of depression, musculoskeletal symptoms, weakness, and gastroesophageal reflux disease in group III patients. CONCLUSIONS: BMI positively correlated with parathyroid tumor weight independent of vitamin D. Severely obese patients have larger parathyroid tumor weight, higher pre- and postoperative PTH, and greater symptoms.

Authors
Adam, MA; Untch, BR; Danko, ME; Stinnett, S; Dixit, D; Koh, J; Marks, JR; Olson, JA
MLA Citation
Adam, MA, Untch, BR, Danko, ME, Stinnett, S, Dixit, D, Koh, J, Marks, JR, and Olson, JA. "Severe obesity is associated with symptomatic presentation, higher parathyroid hormone levels, and increased gland weight in primary hyperparathyroidism." J Clin Endocrinol Metab 95.11 (November 2010): 4917-4924.
PMID
20685860
Source
pubmed
Published In
Journal of Clinical Endocrinology and Metabolism
Volume
95
Issue
11
Publish Date
2010
Start Page
4917
End Page
4924
DOI
10.1210/jc.2010-0666

Urinary biomarkers of oxidative status in a clinical model of oxidative assault.

BACKGROUND: We used doxorubicin-based chemotherapy as a clinical model of oxidative assault in humans. METHODS: The study recruited newly diagnosed breast cancer patients (n = 23). Urine samples were collected immediately before (T0) and at 1 hour (T1) and 24 hours (T24) after i.v. administration of treatment. Measurements included allantoin and the isoprostanes iPF(2alpha)-III, iPF(2alpha)-VI, and 8,12-iso-iPF(2alpha)-VI along with the prostaglandin 2,3-dinor-iPF(2alpha)-III, a metabolite of iPF(2alpha)-III. All biomarkers were quantified using liquid chromatography-tandem mass spectrometry. RESULTS: In all subjects, the levels of the biomarkers increased at T1: allantoin by 22% (P = 0.06), iPF(2alpha)-III by 62% (P < 0.05), iPF(2alpha)-VI by 41% (P < 0.05), 8,12-iso-iPF(2alpha)-VI by 58% (P < 0.05), and 2,3-dinor-iPF(2alpha)-III by 52% (P < 0.05). At T24, the F2-isoprostanes returned to their baseline levels; the levels of allantoin continued to increase, although the T24-T0 difference was not statistically significant. CONCLUSIONS: These results indicate that urinary F2-isoprostanes are valid biomarkers and allantoin is a promising biomarker of oxidative status in humans. IMPACT: The levels of biomarkers change quickly in response to oxidative assault and can be used to monitor oxidative status in humans in response to treatments related either to generation of free radicals (chemotherapy and radiation therapy) or to antioxidants (inborn metabolic diseases and Down syndrome).

Authors
Il'yasova, D; Spasojevic, I; Wang, F; Tolun, AA; Base, K; Young, SP; Marcom, PK; Marks, J; Mixon, G; DiGiulio, R; Millington, DS
MLA Citation
Il'yasova, D, Spasojevic, I, Wang, F, Tolun, AA, Base, K, Young, SP, Marcom, PK, Marks, J, Mixon, G, DiGiulio, R, and Millington, DS. "Urinary biomarkers of oxidative status in a clinical model of oxidative assault." Cancer Epidemiol Biomarkers Prev 19.6 (June 2010): 1506-1510.
PMID
20501773
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
19
Issue
6
Publish Date
2010
Start Page
1506
End Page
1510
DOI
10.1158/1055-9965.EPI-10-0211

Expression signatures of TP53 mutations in serous ovarian cancers.

BACKGROUND: Mutations in the TP53 gene are extremely common and occur very early in the progression of serous ovarian cancers. Gene expression patterns that relate to mutational status may provide insight into the etiology and biology of the disease. METHODS: The TP53 coding region was sequenced in 89 frozen serous ovarian cancers, 40 early stage (I/II) and 49 advanced stage (III/IV). Affymetrix U133A expression data was used to define gene expression patterns by mutation, type of mutation, and cancer stage. RESULTS: Missense or chain terminating (null) mutations in TP53 were found in 59/89 (66%) ovarian cancers. Early stage cancers had a significantly higher rate of null mutations than late stage disease (38% vs. 8%, p < 0.03). In advanced stage cases, mutations were more prevalent in short term survivors than long term survivors (81% vs. 30%, p = 0.0004). Gene expression patterns had a robust ability to predict TP53 status within training data. By using early versus late stage disease for out of sample predictions, the signature derived from early stage cancers could accurately (86%) predict mutation status of late stage cancers. CONCLUSIONS: This represents the first attempt to define a genomic signature of TP53 mutation in ovarian cancer. Patterns of gene expression characteristic of TP53 mutation could be discerned and included several genes that are known p53 targets or have been described in the context of expression signatures of TP53 mutation in breast cancer.

Authors
Bernardini, MQ; Baba, T; Lee, PS; Barnett, JC; Sfakianos, GP; Secord, AA; Murphy, SK; Iversen, E; Marks, JR; Berchuck, A
MLA Citation
Bernardini, MQ, Baba, T, Lee, PS, Barnett, JC, Sfakianos, GP, Secord, AA, Murphy, SK, Iversen, E, Marks, JR, and Berchuck, A. "Expression signatures of TP53 mutations in serous ovarian cancers. (Published online)" BMC Cancer 10 (May 26, 2010): 237-.
Website
http://hdl.handle.net/10161/4356
PMID
20504346
Source
pubmed
Published In
BMC Cancer
Volume
10
Publish Date
2010
Start Page
237
DOI
10.1186/1471-2407-10-237

Intratumor heterogeneity and precision of microarray-based predictors of breast cancer biology and clinical outcome.

PURPOSE: Identifying sources of variation in expression microarray data and the effect of variance in gene expression measurements on complex predictive and diagnostic models is essential when translating microarray-based experimental approaches into clinical assays. The technical reproducibility of microarray platforms is well established. Here, we investigate the additional impact of intratumor heterogeneity, a largely unstudied component of variance, on the performance of several microarray-based assays in breast cancer. PATIENTS AND METHODS: Genome-wide expression profiling was performed on 50 core needle biopsies from 18 breast cancer patients using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Global profiles of expression were characterized using unsupervised clustering methods and variance components models. Array-based measures of estrogen receptor (ER) and progesterone receptor (PR) status were compared with immunohistochemistry. The precision of genomic predictors of ER pathway status, recurrence risk, and sensitivity to chemotherapeutics was evaluated by interclass correlation. RESULTS: Global patterns of gene expression demonstrated that intratumor variation was substantially less than the total variation observed across the patient population. Nevertheless, a fraction of genes exhibited significant intratumor heterogeneity in expression. A high degree of reproducibility was observed in single-gene predictors of ER (intraclass correlation coefficient [ICC] = 0.94) and PR expression (ICC = 0.90), and in a multigene predictor of ER pathway activation (ICC = 0.98) with high concordance with immunohistochemistry. Substantial agreement was also observed for multigene signatures of cancer recurrence (ICC = 0.71) and chemotherapeutic sensitivity (ICC = 0.72 and 0.64). CONCLUSION: Intratumor heterogeneity, although present at the level of individual gene expression, does not preclude precise microarray-based predictions of tumor behavior or clinical outcome in breast cancer patients.

Authors
Barry, WT; Kernagis, DN; Dressman, HK; Griffis, RJ; Hunter, JD; Olson, JA; Marks, JR; Ginsburg, GS; Marcom, PK; Nevins, JR; Geradts, J; Datto, MB
MLA Citation
Barry, WT, Kernagis, DN, Dressman, HK, Griffis, RJ, Hunter, JD, Olson, JA, Marks, JR, Ginsburg, GS, Marcom, PK, Nevins, JR, Geradts, J, and Datto, MB. "Intratumor heterogeneity and precision of microarray-based predictors of breast cancer biology and clinical outcome." J Clin Oncol 28.13 (May 1, 2010): 2198-2206.
PMID
20368555
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
28
Issue
13
Publish Date
2010
Start Page
2198
End Page
2206
DOI
10.1200/JCO.2009.26.7245

Improved staging in node-positive breast cancer patients using lymph node ratio: results in 1,788 patients with long-term follow-up.

BACKGROUND: Axillary lymph node status remains the most important prognostic factor in breast cancer. Established staging systems emphasize the absolute number of positive nodes, without regard for the total number of lymph nodes examined. We sought to confirm that a ratio of positive nodes to total nodes examined (LNR) has prognostic value beyond the current TNM classification for women with node-positive breast cancer. STUDY DESIGN: Using the Duke University Medical Center breast cancer tumor registry, we identified women diagnosed with node-positive breast cancer between 1985 and 2005 (n = 1,788). Variables analyzed for impact on disease-free survival (DFS) included the number of positive nodes, N classification, and the calculated LNR. Based on LNR, the patients were divided into low- (< or =0.2), intermediate- (>0.2 and < or =0.65), and high- (>0.65) risk groups. Kaplan-Meier survival analysis was performed with groups compared by the log-rank test. Values of p < 0.05 were considered significant. RESULTS: For all patients, the 10-year actuarial DFS rates for the low-, intermediate-, and high-risk LNR groups were 69%, 60%, and 45%, respectively. The DFS curves for the 3 LNR groups were significantly different (p < 0.0001). Furthermore, when patients were stratified by pN status, the DFS curves for the LNR groups remained significantly different. The LNR discerned groups of patients with divergent survival probabilities across all pN groups. CONCLUSIONS: Our data show that LNR has prognostic value in assessing breast cancer survival beyond the current TNM classification. This study supports the inclusion of LNR for enhanced risk stratification beyond traditional pN classification.

Authors
Danko, ME; Bennett, KM; Zhai, J; Marks, JR; Olson, JA
MLA Citation
Danko, ME, Bennett, KM, Zhai, J, Marks, JR, and Olson, JA. "Improved staging in node-positive breast cancer patients using lymph node ratio: results in 1,788 patients with long-term follow-up." J Am Coll Surg 210.5 (May 2010): 797-807.
PMID
20421053
Source
pubmed
Published In
Journal of the American College of Surgeons
Volume
210
Issue
5
Publish Date
2010
Start Page
797
End Page
807
DOI
10.1016/j.jamcollsurg.2010.02.045

Association between DNA damage response and repair genes and risk of invasive serous ovarian cancer.

BACKGROUND: We analyzed the association between 53 genes related to DNA repair and p53-mediated damage response and serous ovarian cancer risk using case-control data from the North Carolina Ovarian Cancer Study (NCOCS), a population-based, case-control study. METHODS/PRINCIPAL FINDINGS: The analysis was restricted to 364 invasive serous ovarian cancer cases and 761 controls of white, non-Hispanic race. Statistical analysis was two staged: a screen using marginal Bayes factors (BFs) for 484 SNPs and a modeling stage in which we calculated multivariate adjusted posterior probabilities of association for 77 SNPs that passed the screen. These probabilities were conditional on subject age at diagnosis/interview, batch, a DNA quality metric and genotypes of other SNPs and allowed for uncertainty in the genetic parameterizations of the SNPs and number of associated SNPs. Six SNPs had Bayes factors greater than 10 in favor of an association with invasive serous ovarian cancer. These included rs5762746 (median OR(odds ratio)(per allele) = 0.66; 95% credible interval (CI) = 0.44-1.00) and rs6005835 (median OR(per allele) = 0.69; 95% CI = 0.53-0.91) in CHEK2, rs2078486 (median OR(per allele) = 1.65; 95% CI = 1.21-2.25) and rs12951053 (median OR(per allele) = 1.65; 95% CI = 1.20-2.26) in TP53, rs411697 (median OR (rare homozygote) = 0.53; 95% CI = 0.35 - 0.79) in BACH1 and rs10131 (median OR( rare homozygote) = not estimable) in LIG4. The six most highly associated SNPs are either predicted to be functionally significant or are in LD with such a variant. The variants in TP53 were confirmed to be associated in a large follow-up study. CONCLUSIONS/SIGNIFICANCE: Based on our findings, further follow-up of the DNA repair and response pathways in a larger dataset is warranted to confirm these results.

Authors
Schildkraut, JM; Iversen, ES; Wilson, MA; Clyde, MA; Moorman, PG; Palmieri, RT; Whitaker, R; Bentley, RC; Marks, JR; Berchuck, A
MLA Citation
Schildkraut, JM, Iversen, ES, Wilson, MA, Clyde, MA, Moorman, PG, Palmieri, RT, Whitaker, R, Bentley, RC, Marks, JR, and Berchuck, A. "Association between DNA damage response and repair genes and risk of invasive serous ovarian cancer. (Published online)" PLoS One 5.4 (April 8, 2010): e10061-.
Website
http://hdl.handle.net/10161/8883
PMID
20386703
Source
pubmed
Published In
PloS one
Volume
5
Issue
4
Publish Date
2010
Start Page
e10061
DOI
10.1371/journal.pone.0010061

An adenoviral vaccine encoding full-length inactivated human Her2 exhibits potent immunogenicty and enhanced therapeutic efficacy without oncogenicity.

PURPOSE: Overexpression of the breast cancer oncogene HER2 correlates with poor survival. Current HER2-directed therapies confer limited clinical benefits and most patients experience progressive disease. Because refractory tumors remain strongly HER2+, vaccine approaches targeting HER2 have therapeutic potential, but wild type (wt) HER2 cannot safely be delivered in immunogenic viral vectors because it is a potent oncogene. We designed and tested several HER2 vaccines devoid of oncogenic activity to develop a safe vaccine for clinical use. EXPERIMENTAL DESIGN: We created recombinant adenoviral vectors expressing the extracellular domain of HER2 (Ad-HER2-ECD), ECD plus the transmembrane domain (Ad-HER2-ECD-TM), and full-length HER2 inactivated for kinase function (Ad-HER2-ki), and determined their immunogenicity and antitumor effect in wild type (WT) and HER2-tolerant mice. To assess their safety, we compared their effect on the cellular transcriptome, cell proliferation, anchorage-dependent growth, and transformation potential in vivo. RESULTS: Ad-HER2-ki was the most immunogenic vector in WT animals, retained immunogenicity in HER2-transgenic tolerant animals, and showed strong therapeutic efficacy in treatment models. Despite being highly expressed, HER2-ki protein was not phosphorylated and did not produce an oncogenic gene signature in primary human cells. Moreover, in contrast to HER2-wt, cells overexpressing HER2-ki were less proliferative, displayed less anchorage-independent growth, and were not transformed in vivo. CONCLUSIONS: Vaccination with mutationally inactivated, nononcogenic Ad-HER2-ki results in robust polyclonal immune responses to HER2 in tolerant models, which translates into strong and effective antitumor responses in vivo. Ad-HER2-ki is thus a safe and promising vaccine for evaluation in clinical trials.

Authors
Hartman, ZC; Wei, J; Osada, T; Glass, O; Lei, G; Yang, X-Y; Peplinski, S; Kim, D-W; Xia, W; Spector, N; Marks, J; Barry, W; Hobeika, A; Devi, G; Amalfitano, A; Morse, MA; Lyerly, HK; Clay, TM
MLA Citation
Hartman, ZC, Wei, J, Osada, T, Glass, O, Lei, G, Yang, X-Y, Peplinski, S, Kim, D-W, Xia, W, Spector, N, Marks, J, Barry, W, Hobeika, A, Devi, G, Amalfitano, A, Morse, MA, Lyerly, HK, and Clay, TM. "An adenoviral vaccine encoding full-length inactivated human Her2 exhibits potent immunogenicty and enhanced therapeutic efficacy without oncogenicity." Clin Cancer Res 16.5 (March 1, 2010): 1466-1477.
PMID
20179231
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
16
Issue
5
Publish Date
2010
Start Page
1466
End Page
1477
DOI
10.1158/1078-0432.CCR-09-2549

Ovarian cancer tumor infiltrating T-regulatory (T(reg)) cells are associated with a metastatic phenotype.

OBJECTIVE: The objective of this study was to examine the clinicopathologic correlates of T-regulatory (T(reg)) cell infiltration in serous ovarian cancers and to define gene signatures associated with high T(reg)s. METHODS: Tumor infiltrating T(reg) and cytotoxic T-cells (CTLs) were quantitated in 232 primary serous ovarian cancers by immunostaining for FOXP3 and CD8. Expression microarray analysis was performed in a subset of 48 advanced cancers with the highest and lowest numbers of infiltrating T(reg)s and a genomic signature was developed using binary regression. ANOVA analysis was performed to assess the most differentially expressed genes and these genes were further assessed using Ingenuity Pathway Analysis (IPA) software. RESULTS: High T(reg) infiltration in ovarian cancers was associated with high grade (p<0.0001), advanced stage (p=0.004) and suboptimal debulking (p<0.04), but not with survival. In contrast, high tumor infiltrating CD8 CTL infiltration was associated with favorable survival (median survival 48.7 vs. 34.6 months, p=0.01). A microarray-based genomic signature for high tumor-infiltrating T(reg) cells had a 77% predictive accuracy using leave-one-out cross-validation. ANOVA of microarray data revealed the antigen presentation pathway as the most differentially expressed canonical pathway (p<0.00001) between cancers with high and low T(reg) cells. CONCLUSIONS: These data suggest that there may be an association between increased T(reg) cell infiltration in ovarian cancers and advanced stage. Increased T(reg) infiltration is characterized by a genomic signature enriched with several immunologic pathway genes. Therapeutic strategies that reduce tumor infiltrating T(reg) cells are under investigation and may prove useful in ovarian cancers with high numbers of these cells.

Authors
Barnett, JC; Bean, SM; Whitaker, RS; Kondoh, E; Baba, T; Fujii, S; Marks, JR; Dressman, HK; Murphy, SK; Berchuck, A
MLA Citation
Barnett, JC, Bean, SM, Whitaker, RS, Kondoh, E, Baba, T, Fujii, S, Marks, JR, Dressman, HK, Murphy, SK, and Berchuck, A. "Ovarian cancer tumor infiltrating T-regulatory (T(reg)) cells are associated with a metastatic phenotype." Gynecol Oncol 116.3 (March 2010): 556-562.
PMID
20006900
Source
pubmed
Published In
Gynecologic Oncology
Volume
116
Issue
3
Publish Date
2010
Start Page
556
End Page
562
DOI
10.1016/j.ygyno.2009.11.020

Polymorphism in the GALNT1 gene and epithelial ovarian cancer in non-Hispanic white women: the Ovarian Cancer Association Consortium.

Aberrant glycosylation is a well-described hallmark of cancer. In a previous ovarian cancer case control study that examined polymorphisms in 26 glycosylation-associated genes, we found strong statistical evidence (P = 0.00017) that women who inherited two copies of a single-nucleotide polymorphism in the UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase, GALNT1, had decreased ovarian cancer risk. The current study attempted to replicate this observation. The GALNT1 single-nucleotide polymorphism rs17647532 was genotyped in 6,965 cases and 8,377 controls from 14 studies forming the Ovarian Cancer Association Consortium. The fixed effects estimate per rs17647532 allele was null (odds ratio, 0.99; 95% confidence interval, 0.92-1.07). When a recessive model was fit, the results were unchanged. Test for heterogeneity of the odds ratios revealed consistency across the 14 replication sites but significant differences compared with the original study population (P = 0.03). This study underscores the need for replication of putative findings in genetic association studies.

Authors
Phelan, CM; Tsai, Y-Y; Goode, EL; Vierkant, RA; Fridley, BL; Beesley, J; Chen, XQ; Webb, PM; Chanock, S; Cramer, DW; Moysich, K; Edwards, RP; Chang-Claude, J; Garcia-Closas, M; Yang, H; Wang-Gohrke, S; Hein, R; Green, AC; Lissowska, J; Carney, ME; Lurie, G; Wilkens, LR; Ness, RB; Pearce, CL; Wu, AH; Van Den Berg, DJ; Stram, DO; Terry, KL; Whiteman, DC; Whittemore, AS; DiCioccio, RA; McGuire, V; Doherty, JA; Rossing, MA; Anton-Culver, H; Ziogas, A; Hogdall, C; Hogdall, E; Krüger Kjaer, S et al.
MLA Citation
Phelan, CM, Tsai, Y-Y, Goode, EL, Vierkant, RA, Fridley, BL, Beesley, J, Chen, XQ, Webb, PM, Chanock, S, Cramer, DW, Moysich, K, Edwards, RP, Chang-Claude, J, Garcia-Closas, M, Yang, H, Wang-Gohrke, S, Hein, R, Green, AC, Lissowska, J, Carney, ME, Lurie, G, Wilkens, LR, Ness, RB, Pearce, CL, Wu, AH, Van Den Berg, DJ, Stram, DO, Terry, KL, Whiteman, DC, Whittemore, AS, DiCioccio, RA, McGuire, V, Doherty, JA, Rossing, MA, Anton-Culver, H, Ziogas, A, Hogdall, C, Hogdall, E, and Krüger Kjaer, S et al. "Polymorphism in the GALNT1 gene and epithelial ovarian cancer in non-Hispanic white women: the Ovarian Cancer Association Consortium." Cancer Epidemiol Biomarkers Prev 19.2 (February 2010): 600-604.
PMID
20142253
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
19
Issue
2
Publish Date
2010
Start Page
600
End Page
604
DOI
10.1158/1055-9965.EPI-09-0861

Tumor Sampling Variables Affect Reproducibility of Predictive Gene Expression Signatures in Breast Cancer

Authors
Untch, BR; Adam, MA; Tebbit, CL; Marks, JR; Olson, JA
MLA Citation
Untch, BR, Adam, MA, Tebbit, CL, Marks, JR, and Olson, JA. "Tumor Sampling Variables Affect Reproducibility of Predictive Gene Expression Signatures in Breast Cancer." February 2010.
Source
wos-lite
Published In
Annals of Surgical Oncology
Volume
17
Publish Date
2010
Start Page
S30
End Page
S30

IGF2R polymorphisms and risk of esophageal and gastric adenocarcinomas (International Journal of Cancer (2009) 125, (2673-2678))

Authors
Hoyo, C; Schildkraut, JM; Murph, SK; Chow, WH; Vaughan, TL; Risch, H; Marks, JR; Jirtle, RL; Calingeart, B; Mayne, S; Jr, JF; Gammon, MD
MLA Citation
Hoyo, C, Schildkraut, JM, Murph, SK, Chow, WH, Vaughan, TL, Risch, H, Marks, JR, Jirtle, RL, Calingeart, B, Mayne, S, Jr, JF, and Gammon, MD. "IGF2R polymorphisms and risk of esophageal and gastric adenocarcinomas (International Journal of Cancer (2009) 125, (2673-2678))." International Journal of Cancer 126.3 (2010): 799--.
Source
scival
Published In
International Journal of Cancer
Volume
126
Issue
3
Publish Date
2010
Start Page
799-
DOI
10.1002/ijc.24975

Development of a multimarker assay for early detection of ovarian cancer

Purpose: Early detection of ovarian cancer has great promise to improve clinical outcome. Patients and Methods: Ninety-six serum biomarkers were analyzed in sera from healthy women and from patients with ovarian cancer, benign pelvic tumors, and breast, colorectal, and lung cancers, using multiplex xMAP bead-based immunoassays. A Metropolis algorithm with Monte Carlo simulation (MMC) was used for analysis of the data. Results: A training set, including sera from 139 patients with early-stage ovarian cancer, 149 patients with late-stage ovarian cancer, and 1,102 healthy women, was analyzed with MMC algorithm and cross validation to identify an optimal biomarker panel discriminating early-stage cancer from healthy controls. The four-biomarker panel providing the highest diagnostic power of 86% sensitivity (SN) for early-stage and 93% SN for late-stage ovarian cancer at 98% specificity (SP) was comprised of CA-125, HE4, CEA, and VCAM-1. This model was applied to an independent blinded validation set consisting of sera from 44 patients with early-stage ovarian cancer, 124 patients with late-stage ovarian cancer, and 929 healthy women, providing unbiased estimates of 86% SN for stage I and II and 95% SN for stage III and IV disease at 98% SP. This panel was selective for ovarian cancer showing SN of 33% for benign pelvic disease, SN of 6% for breast cancer, SN of 0% for colorectal cancer, and SN of 36% for lung cancer. Conclusion: A panel of CA-125, HE4, CEA, and VCAM-1, after additional validation, could serve as an initial stage in a screening strategy for epithelial ovarian cancer. © 2010 by American Society of Clinical Oncology.

Authors
Yurkovetsky, Z; Skates, S; Lomakin, A; Nolen, B; Pulsipher, T; Modugno, F; Marks, J; Godwin, A; Gorelik, E; Jacobs, I; Menon, U; Lu, K; Badgwell, D; Jr, RCB; Lokshin, AE
MLA Citation
Yurkovetsky, Z, Skates, S, Lomakin, A, Nolen, B, Pulsipher, T, Modugno, F, Marks, J, Godwin, A, Gorelik, E, Jacobs, I, Menon, U, Lu, K, Badgwell, D, Jr, RCB, and Lokshin, AE. "Development of a multimarker assay for early detection of ovarian cancer." Journal of Clinical Oncology 28.13 (2010): 2159-2166.
PMID
20368574
Source
scival
Published In
Journal of Clinical Oncology
Volume
28
Issue
13
Publish Date
2010
Start Page
2159
End Page
2166
DOI
10.1200/JCO.2008.19.2484

IGF2R polymorphisms and risk of esophageal and gastric adenocarcinomas.

The mannose-6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) encodes a protein that plays a critical role in tumor suppression, in part by modulating bioavailability of a potent mitogen, insulin-like growth factor-2 (IGF2). We tested the hypothesis that the common nonsynonymous genetic variants in M6P/IGF2R c.901C > G (Leu > Val) in exon 6 and c.5002G > A (Gly > Arg) in exon 34 are associated with risk of esophageal and gastric cancers. Study participants in this population-based study comprise 197 controls and 182 cases, including 105 with esophageal-gastric cardia adenocarcinoma (EGA), 57 with noncardia gastric adenocarcinoma and 20 with esophageal squamous (ES) cell carcinoma. Among white males, odds ratios (ORs) were elevated in relation to carrying at least 1 c.901C > G allele for EGA [OR = 1.9; 95% confidence intervals (CIs) = 1.0-3.6] and noncardia gastric cancer (OR = 2.5; 95% CI = 1.2-5.5), but not ES. Exploratory subgroup analyses suggested that associations between EGA and this variant were stronger among irregular or nonusers of nonsteroidal anti-inflammatory drugs (NSAIDs) (OR = 2.3; 95% CI = 1.2-4.2) and cigarette smokers (OR = 2.1; 95% CI = 1.0-4.2). An association between carrying the c.5002G > A genotype and EGA was not evident. These findings suggest that nonsynonymous polymorphisms in M6P/IGF2R may contribute to the risks of EGA and noncardia adenocarcinomas. Larger studies are required to confirm these findings.

Authors
Hoyo, C; Schildkraut, JM; Murphy, SK; Chow, W-H; Vaughan, TL; Risch, H; Marks, JR; Jirtle, RL; Calingaert, B; Mayne, S; Fraumeni, J; Gammon, MD
MLA Citation
Hoyo, C, Schildkraut, JM, Murphy, SK, Chow, W-H, Vaughan, TL, Risch, H, Marks, JR, Jirtle, RL, Calingaert, B, Mayne, S, Fraumeni, J, and Gammon, MD. "IGF2R polymorphisms and risk of esophageal and gastric adenocarcinomas." Int J Cancer 125.11 (December 1, 2009): 2673-2678.
PMID
19626700
Source
pubmed
Published In
International Journal of Cancer
Volume
125
Issue
11
Publish Date
2009
Start Page
2673
End Page
2678
DOI
10.1002/ijc.24623

Novel tumor sampling strategies to enable microarray gene expression signatures in breast cancer: a study to determine feasibility and reproducibility in the context of clinical care.

Feasibility and reproducibility of microarray biomarkers in clinical settings are doubted because of reliance on fresh frozen tissue. We sought to develop and validate a paradigm of frozen tissue collection from early breast tumors to enable use of microarray in oncology practice. Frozen core needle biopsies (CNBx) were collected from 150 clinical stage I patients during image-guided diagnostic biopsy and/or surgery. Histology and tumor content from frozen cores were compared to diagnostic specimens. Twenty-eight patients had microarray analysis to examine accuracy and reproducibility of predictive gene signatures developed for estrogen receptor (ER) and HER2. One hundred twenty-seven (85%) of 150 patients had at least one frozen core containing cancer suitable for microarray analysis. Larger tumor size, ex vivo biopsy, and use of a new specimen device increased the likelihood of obtaining adequate specimens. Sufficient quality RNA was obtained from 90% of tumor cores. Microarray signatures predicting ER and HER2 expression were developed in training sets of up to 363 surgical samples and were applied to microarray data obtained from core samples collected in clinical settings. In these samples, prediction of ER and HER2 expression achieved a sensitivity/specificity of 94%/100%, and 82%/72%, respectively. Predictions were reproducible in 83-100% of paired samples. Frozen CNBx can be readily obtained from most breast cancers without interfering with pathologic evaluation in routine clinical settings. Collection of tumor tissue at diagnostic biopsy and/or at surgery from lumpectomy specimens using image guidance resulted in sufficient samples for array analysis from over 90% of patients. Sampling of breast cancer for microarray data is reproducible and feasible in clinical practice and can yield signatures predictive of multiple breast cancer phenotypes.

Authors
Tebbit, CL; Zhai, J; Untch, BR; Ellis, MJ; Dressman, HK; Bentley, RC; Baker, JA; Marcom, PK; Nevins, JR; Marks, JR; Olson, JA
MLA Citation
Tebbit, CL, Zhai, J, Untch, BR, Ellis, MJ, Dressman, HK, Bentley, RC, Baker, JA, Marcom, PK, Nevins, JR, Marks, JR, and Olson, JA. "Novel tumor sampling strategies to enable microarray gene expression signatures in breast cancer: a study to determine feasibility and reproducibility in the context of clinical care." Breast Cancer Res Treat 118.3 (December 2009): 635-643.
PMID
19224362
Source
pubmed
Published In
Breast Cancer Research and Treatment
Volume
118
Issue
3
Publish Date
2009
Start Page
635
End Page
643
DOI
10.1007/s10549-008-0301-1

Markers of oxidative status in a clinical model of oxidative assault: a pilot study in human blood following doxorubicin administration.

We used doxorubicin-based chemotherapy as a clinical model for oxidative assault. Study recruited 23 breast cancer patients and collected blood samples before (T0), at 1 (T1) and 24 hours (T24) after treatment administration. Measurements included protein carbonyl content (PPCC), malondialdehyde (MDA), and alpha- and gamma-tocopherols in plasma and total glutathione content in erythrocytes (erGSHt). In all subjects, PPCC and MDA levels did not change. erGSHt levels increased at T24 by 8% (p=0.03). Levels of alpha, gamma, and total tocopherols progressively decreased by 7%-15% (p <0.05). In subjects with low erGSHt levels (below median), PPCC mean levels progressively increased from 0.35 (T0) to 0.56 (T1) and 0.72 nmol carbonyl/mg protein (T24) (p =0.2). These results indicate that (1) plasma MDA is not a sensitive biomarker in humans; (2) PPCC potentially may be used, if antioxidant reserves are taken into account; (3) antioxidant reserves play an important role in the reaction to oxidative stress.

Authors
Il'yasova, D; Mixon, G; Wang, F; Marcom, PK; Marks, J; Spasojevich, I; Craft, N; Arredondo, F; DiGiulio, R
MLA Citation
Il'yasova, D, Mixon, G, Wang, F, Marcom, PK, Marks, J, Spasojevich, I, Craft, N, Arredondo, F, and DiGiulio, R. "Markers of oxidative status in a clinical model of oxidative assault: a pilot study in human blood following doxorubicin administration." Biomarkers 14.5 (August 2009): 321-325.
PMID
19476408
Source
pubmed
Published In
Biomarkers (Informa)
Volume
14
Issue
5
Publish Date
2009
Start Page
321
End Page
325
DOI
10.1080/13547500902946757

Predictors of variation in serum IGF1 and IGFBP3 levels in healthy African American and white men.

BACKGROUND: Individual variation in circulating insulinlike growth factor-1 (IGF1) and its major binding protein, insulinlike growth factor binding protein-3 (IGFBP3), have been etiologically linked to several chronic diseases, including some cancers. Factors associated with variation in circulating levels of these peptide hormones remain unclear. METHODS: Multiple linear regression models were used to determine the extent to which sociodemographic characteristics, lifestyle factors, personal and family history of chronic disease, and common genetic variants, the (CA)n repeat polymorphism in the IGF1 promoter and the IGFBP3-202 A/C polymorphism (rs2854744) predict variation in IGF1 or IGFBP3 serum levels in 33 otherwise healthy African American and 37 white males recruited from Durham Veterans Administration Medical Center. RESULTS: Predictors of serum IGF1, IGFBP3, and the IGF1:IGFBP3 molar ratio varied by race. In African Americans, 17% and 28% of the variation in serum IGF1 and the IGF1:IGFBP3 molar ratio, were explained by cigarette smoking and carrying the IGF1 (CA)19 repeat allele, respectively. Not carrying at least 1 IGF1 (CA)19 repeat allele and a high body mass index explained 8% and 14%, respectively, of the variation IGFBP3 levels. These factors did not predict variation of these peptides in whites. CONCLUSION: If successfully replicated in larger studies, these findings would add to recent evidence, suggesting known genetic and lifestyle chronic disease risk factors influence IGF1 and IGFBP3 circulating levels differently in African Americans and whites.

Authors
Hoyo, C; Grubber, J; Demark-Wahnefried, W; Lobaugh, B; Jeffreys, AS; Grambow, SC; Marks, JR; Keku, TO; Walther, PJ; Schildkraut, JM
MLA Citation
Hoyo, C, Grubber, J, Demark-Wahnefried, W, Lobaugh, B, Jeffreys, AS, Grambow, SC, Marks, JR, Keku, TO, Walther, PJ, and Schildkraut, JM. "Predictors of variation in serum IGF1 and IGFBP3 levels in healthy African American and white men." J Natl Med Assoc 101.7 (July 2009): 711-716.
PMID
19634593
Source
pubmed
Published In
Journal of the National Medical Association
Volume
101
Issue
7
Publish Date
2009
Start Page
711
End Page
716

Comparative genome-wide screening identifies a conserved doxorubicin repair network that is diploid specific in Saccharomyces cerevisiae.

The chemotherapeutic doxorubicin (DOX) induces DNA double-strand break (DSB) damage. In order to identify conserved genes that mediate DOX resistance, we screened the Saccharomyces cerevisiae diploid deletion collection and identified 376 deletion strains in which exposure to DOX was lethal or severely reduced growth fitness. This diploid screen identified 5-fold more DOX resistance genes than a comparable screen using the isogenic haploid derivative. Since DSB damage is repaired primarily by homologous recombination in yeast, and haploid cells lack an available DNA homolog in G1 and early S phase, this suggests that our diploid screen may have detected the loss of repair functions in G1 or early S phase prior to complete DNA replication. To test this, we compared the relative DOX sensitivity of 30 diploid deletion mutants identified under our screening conditions to their isogenic haploid counterpart, most of which (n = 26) were not detected in the haploid screen. For six mutants (bem1Delta, ctf4Delta, ctk1Delta, hfi1Delta,nup133Delta, tho2Delta) DOX-induced lethality was absent or greatly reduced in the haploid as compared to the isogenic diploid derivative. Moreover, unlike WT, all six diploid mutants displayed severe G1/S phase cell cycle progression defects when exposed to DOX and some were significantly enhanced (ctk1Delta and hfi1Delta) or deficient (tho2Delta) for recombination. Using these and other "THO2-like" hypo-recombinogenic, diploid-specific DOX sensitive mutants (mft1Delta, thp1Delta, thp2Delta) we utilized known genetic/proteomic interactions to construct an interactive functional genomic network which predicted additional DOX resistance genes not detected in the primary screen. Most (76%) of the DOX resistance genes detected in this diploid yeast screen are evolutionarily conserved suggesting the human orthologs are candidates for mediating DOX resistance by impacting on checkpoint and recombination functions in G1 and/or early S phases.

Authors
Westmoreland, TJ; Wickramasekara, SM; Guo, AY; Selim, AL; Winsor, TS; Greenleaf, AL; Blackwell, KL; Olson, JA; Marks, JR; Bennett, CB
MLA Citation
Westmoreland, TJ, Wickramasekara, SM, Guo, AY, Selim, AL, Winsor, TS, Greenleaf, AL, Blackwell, KL, Olson, JA, Marks, JR, and Bennett, CB. "Comparative genome-wide screening identifies a conserved doxorubicin repair network that is diploid specific in Saccharomyces cerevisiae. (Published online)" PLoS One 4.6 (June 8, 2009): e5830-.
PMID
19503795
Source
pubmed
Published In
PloS one
Volume
4
Issue
6
Publish Date
2009
Start Page
e5830
DOI
10.1371/journal.pone.0005830

Microarray analysis of early stage serous ovarian cancers shows profiles predictive of favorable outcome.

PURPOSE: Although few women with advanced serous ovarian cancer are cured, detection of the disease at an early stage is associated with a much higher likelihood of survival. We previously used gene expression array analysis to distinguish subsets of advanced cancers based on disease outcome. In the present study, we report on gene expression of early-stage cancers and validate our prognostic model for advanced-stage cancers. EXPERIMENTAL DESIGN: Frozen specimens from 39 stage I/II, 42 stage III/IV, and 20 low malignant potential cancers were obtained from four different sites. A linear discriminant model was used to predict survival based upon array data. RESULTS: We validated the late-stage survival model and show that three of the most differentially expressed genes continue to be predictive of outcome. Most early-stage cancers (38 of 39 invasive, 15 of 20 low malignant potential) were classified as long-term survivors (median probabilities 0.97 and 0.86). MAL, the most differentially expressed gene, was further validated at the protein level and found to be an independent predictor of poor survival in an unselected group of advanced serous cancers (P = 0.0004). CONCLUSIONS: These data suggest that serous ovarian cancers detected at an early stage generally have a favorable underlying biology similar to advanced-stage cases that are long-term survivors. Conversely, most late-stage ovarian cancers seem to have a more virulent biology. This insight suggests that if screening approaches are to succeed it will be necessary to develop approaches that are able to detect these virulent cancers at an early stage.

Authors
Berchuck, A; Iversen, ES; Luo, J; Clarke, JP; Horne, H; Levine, DA; Boyd, J; Alonso, MA; Secord, AA; Bernardini, MQ; Barnett, JC; Boren, T; Murphy, SK; Dressman, HK; Marks, JR; Lancaster, JM
MLA Citation
Berchuck, A, Iversen, ES, Luo, J, Clarke, JP, Horne, H, Levine, DA, Boyd, J, Alonso, MA, Secord, AA, Bernardini, MQ, Barnett, JC, Boren, T, Murphy, SK, Dressman, HK, Marks, JR, and Lancaster, JM. "Microarray analysis of early stage serous ovarian cancers shows profiles predictive of favorable outcome." Clin Cancer Res 15.7 (April 1, 2009): 2448-2455.
PMID
19318476
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
7
Publish Date
2009
Start Page
2448
End Page
2455
DOI
10.1158/1078-0432.CCR-08-2430

Single nucleotide polymorphisms in the TP53 region and susceptibility to invasive epithelial ovarian cancer

The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNP) in the tps3 region. Significant findings from this discovery phase were followed up for replication in the other OCAC studies. Mixed effects logistic regression was used to generate posterior median per allele odds ratios (OR), 95% probability intervals (PI), and Bayes factors (BF) for genotype associations. Five SMPs showed significant associations with risk in one or more of the discovery investigations and were followed up by OCAC. Mixed effects analysis confirmed associations with serous invasive cancers for two correlated (r2 = 0.62) SMPs: rs2287498 (median per allele OB, 1.30; 95% PI, 1.07-1.57) and rsl2951053 (median per allele OR, 1.19; 95% PI, 1.01-1.38). Analyses of other histologic subtypes suggested similar associations with endometrioid but not with mucinous or clear cell cancers. This large study provides statistical evidence for a small increase in risk of ovarian cancer associated with common variants in the TPS3 region. © 2009 American Association for Cancer Research.

Authors
Schildkraut, JM; Goode, EL; Clyde, MA; Iversen, ES; Moorman, PG; Berchuck, A; Marks, JR; Lissowska, J; Brinton, L; Peplonska, B; Cunningham, JM; Vierkant, RA; Rider, DN; Chenevix-Trench, G; Webb, PM; Beesley, J; Chen, X; Phelan, C; Sutphen, R; Sellers, TA; Pearce, L; Wu, AH; Van Berg, DD; Conti, D; Elund, CK; Anderson, R; Goodman, MT; Lurie, G; Carney, ME; Thompson, PJ; Gayther, SA; Ramus, SJ; Jacobs, I; Kjaer, SK; Hogdall, E; Blaakaer, J; Hogdall, C; Easton, DF; Song, H; Pharoah, PDP et al.
MLA Citation
Schildkraut, JM, Goode, EL, Clyde, MA, Iversen, ES, Moorman, PG, Berchuck, A, Marks, JR, Lissowska, J, Brinton, L, Peplonska, B, Cunningham, JM, Vierkant, RA, Rider, DN, Chenevix-Trench, G, Webb, PM, Beesley, J, Chen, X, Phelan, C, Sutphen, R, Sellers, TA, Pearce, L, Wu, AH, Van Berg, DD, Conti, D, Elund, CK, Anderson, R, Goodman, MT, Lurie, G, Carney, ME, Thompson, PJ, Gayther, SA, Ramus, SJ, Jacobs, I, Kjaer, SK, Hogdall, E, Blaakaer, J, Hogdall, C, Easton, DF, Song, H, and Pharoah, PDP et al. "Single nucleotide polymorphisms in the TP53 region and susceptibility to invasive epithelial ovarian cancer." Cancer Research 69.6 (March 15, 2009): 2349-2357.
PMID
19276375
Source
scopus
Published In
Cancer Research
Volume
69
Issue
6
Publish Date
2009
Start Page
2349
End Page
2357
DOI
10.1158/0008-5472.CAN-08-2902

Inactivation of the MAL gene in breast cancer is a common event that predicts benefit from adjuvant chemotherapy.

Dysregulation of MAL (myelin and lymphocyte protein) has been implicated in several malignancies including esophageal, ovarian, and cervical cancers. The MAL protein functions in apical transport in polarized epithelial cells; therefore, its disruption may lead to loss of organized polarity characteristic of most solid malignancies. Bisulfite sequencing of the MAL promoter CpG island revealed hypermethylation in breast cancer cell lines and 69% of primary tumors analyzed compared with normal breast epithelial cells. Differential methylation between normal and cancer DNA was confined to the proximal promoter region. In a subset of breast cancer cell lines including T47D and MCF7 cells, promoter methylation correlated with transcriptional silencing that was reversible with the methylation inhibitor 5-aza-2'-deoxycytidine. In addition, expression of MAL reduced motility and resulted in a redistribution of lipid raft components in MCF10A cells. MAL protein expression measured by immunohistochemistry revealed no significant correlation with clinicopathologic features. However, in patients who did not receive adjuvant chemotherapy, reduced MAL expression was a significant predictive factor for disease-free survival. These data implicate MAL as a commonly altered gene in breast cancer with implications for response to chemotherapy.

Authors
Horne, HN; Lee, PS; Murphy, SK; Alonso, MA; Olson, JA; Marks, JR
MLA Citation
Horne, HN, Lee, PS, Murphy, SK, Alonso, MA, Olson, JA, and Marks, JR. "Inactivation of the MAL gene in breast cancer is a common event that predicts benefit from adjuvant chemotherapy." Mol Cancer Res 7.2 (February 2009): 199-209.
PMID
19208741
Source
pubmed
Published In
Molecular cancer research : MCR
Volume
7
Issue
2
Publish Date
2009
Start Page
199
End Page
209
DOI
10.1158/1541-7786.MCR-08-0314

Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells.

The cancer stem cell hypothesis posits that malignant growth arises from a rare population of progenitor cells within a tumor that provide it with unlimited regenerative capacity. Such cells also possess increased resistance to chemotherapeutic agents. Resurgence of chemoresistant disease after primary therapy typifies epithelial ovarian cancer and may be attributable to residual cancer stem cells, or cancer-initiating cells, that survive initial treatment. As the cell surface marker CD133 identifies cancer-initiating cells in a number of other malignancies, we sought to determine the potential role of CD133+ cells in epithelial ovarian cancer. We detected CD133 on ovarian cancer cell lines, in primary cancers and on purified epithelial cells from ascitic fluid of ovarian cancer patients. We found CD133+ ovarian cancer cells generate both CD133+ and CD133- daughter cells, whereas CD133- cells divide symmetrically. CD133+ cells exhibit enhanced resistance to platinum-based therapy, drugs commonly used as first-line agents for the treatment of ovarian cancer. Sorted CD133+ ovarian cancer cells also form more aggressive tumor xenografts at a lower inoculum than their CD133- progeny. Epigenetic changes may be integral to the behavior of cancer progenitor cells and their progeny. In this regard, we found that CD133 transcription is controlled by both histone modifications and promoter methylation. Sorted CD133- ovarian cancer cells treated with DNA methyltransferase and histone deacetylase inhibitors show a synergistic increase in cell surface CD133 expression. Moreover, DNA methylation at the ovarian tissue active P2 promoter is inversely correlated with CD133 transcription. We also found that promoter methylation increases in CD133- progeny of CD133+ cells, with CD133+ cells retaining a less methylated or unmethylated state. Taken together, our results show that CD133 expression in ovarian cancer is directly regulated by epigenetic modifications and support the idea that CD133 demarcates an ovarian cancer-initiating cell population. The activity of these cells may be epigenetically detected and such cells might serve as pertinent chemotherapeutic targets for reducing disease recurrence.

Authors
Baba, T; Convery, PA; Matsumura, N; Whitaker, RS; Kondoh, E; Perry, T; Huang, Z; Bentley, RC; Mori, S; Fujii, S; Marks, JR; Berchuck, A; Murphy, SK
MLA Citation
Baba, T, Convery, PA, Matsumura, N, Whitaker, RS, Kondoh, E, Perry, T, Huang, Z, Bentley, RC, Mori, S, Fujii, S, Marks, JR, Berchuck, A, and Murphy, SK. "Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells." Oncogene 28.2 (January 15, 2009): 209-218.
PMID
18836486
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
28
Issue
2
Publish Date
2009
Start Page
209
End Page
218
DOI
10.1038/onc.2008.374

Her2/neu signaling blockade improves tumor oxygenation in a multifactorial fashion in Her2/neu+ tumors.

PURPOSE: Tumor hypoxia reduces the efficacy of radiation and chemotherapy as well as altering gene expression that promotes cell survival and metastasis. The growth factor receptor, Her2/neu, is overexpressed in 25-30% of breast tumors. Tumors that are Her2(+) may have an altered state of oxygenation, relative to Her2(-) tumors, due to differences in tumor growth rate and angiogenesis. METHODS: Her2 blockade was accomplished using an antibody to the receptor (trastuzumab; Herceptin). This study examined the effects of Her2 blockade on tumor angiogenesis, vascular architecture, and hypoxia in Her2(+) and Her2(-) MCF7 xenograft tumors. RESULTS: Treatment with trastuzumab in Her2(+) tumors significantly improved tumor oxygenation, increased microvessel density, and improved vascular architecture compared with the control-treated Her2(+) tumors. The Her2(+) xenografts treated with trastuzumab also demonstrated decreased proliferation indices when compared with control-treated xenografts. These results indicate that Her2 blockade can improve tumor oxygenation by decreasing oxygen consumption (reducing tumor cell proliferation and inducing necrosis) and increasing oxygen delivery (vascular density and architecture). CONCLUSIONS: These results support the use of trastuzumab as an adjunct in the treatment of breast tumors with chemotherapy or radiotherapy, as improvements in tumor oxygenation should translate into improved treatment response.

Authors
Hardee, ME; Eapen, RJ; Rabbani, ZN; Dreher, MR; Marks, J; Blackwell, KL; Dewhirst, MW
MLA Citation
Hardee, ME, Eapen, RJ, Rabbani, ZN, Dreher, MR, Marks, J, Blackwell, KL, and Dewhirst, MW. "Her2/neu signaling blockade improves tumor oxygenation in a multifactorial fashion in Her2/neu+ tumors." Cancer Chemother Pharmacol 63.2 (January 2009): 219-228.
PMID
18365198
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
63
Issue
2
Publish Date
2009
Start Page
219
End Page
228
DOI
10.1007/s00280-008-0729-3

Do serum biomarkers really measure breast cancer?

BACKGROUND: Because screening mammography for breast cancer is less effective for premenopausal women, we investigated the feasibility of a diagnostic blood test using serum proteins. METHODS: This study used a set of 98 serum proteins and chose diagnostically relevant subsets via various feature-selection techniques. Because of significant noise in the data set, we applied iterated Bayesian model averaging to account for model selection uncertainty and to improve generalization performance. We assessed generalization performance using leave-one-out cross-validation (LOOCV) and receiver operating characteristic (ROC) curve analysis. RESULTS: The classifiers were able to distinguish normal tissue from breast cancer with a classification performance of AUC = 0.82 +/- 0.04 with the proteins MIF, MMP-9, and MPO. The classifiers distinguished normal tissue from benign lesions similarly at AUC = 0.80 +/- 0.05. However, the serum proteins of benign and malignant lesions were indistinguishable (AUC = 0.55 +/- 0.06). The classification tasks of normal vs. cancer and normal vs. benign selected the same top feature: MIF, which suggests that the biomarkers indicated inflammatory response rather than cancer. CONCLUSION: Overall, the selected serum proteins showed moderate ability for detecting lesions. However, they are probably more indicative of secondary effects such as inflammation rather than specific for malignancy.

Authors
Jesneck, JL; Mukherjee, S; Yurkovetsky, Z; Clyde, MA; Marks, JR; Lokshin, AE; Lo, JY
MLA Citation
Jesneck, JL, Mukherjee, S, Yurkovetsky, Z, Clyde, MA, Marks, JR, Lokshin, AE, and Lo, JY. "Do serum biomarkers really measure breast cancer?." BMC cancer 9 (2009): 164-164.
PMID
19476629
Source
manual
Published In
BMC Cancer
Volume
9
Publish Date
2009
Start Page
164
End Page
164
DOI
10.1186/1471-2407-9-164

Role of eotaxin-1 signaling in ovarian cancer

Purpose: Tumor cell growth and migration can be directly regulated by chemokines. In the present study, the association of CCL11 with ovarian cancer has been investigated. Experimental Design and Results: Circulating levels of CCL11 in sera of patients with ovarian cancer were significantly lower than those in healthy women or women with breast, lung, liver, pancreatic, or colon cancer. Cultured ovarian carcinoma cells absorbed soluble CCL11, indicating that absorption by tumor cells could be responsible for the observed reduction of serum level of CCL11 in ovarian cancer. Postoperative CCL11 levels in women with ovarian cancer negatively correlated with relapse-free survival. Ovarian tumors overexpressed three known cognate receptors of CCL11, CC chemokine receptors (CCR) 2, 3, and 5. Strong positive correlation was observed between expression of individual receptors and tumor grade. CCL11 potently stimulated proliferation and migration/invasion of ovarian carcinoma cell lines, and these effects were inhibited by neutralizing antibodies against CCR2, CCR3, and CCR5. The growth-stimulatory effects of CCL11 were likely associated with activation of extracellular signal-regulated kinase 1/2, MEK1, and STAT3 phosphoproteins and with increased production of multiple cytokines, growth factors, and angiogenic factors. Inhibition of CCL11 signaling by the combination of neutralizing antibodies against the ligand and its receptors significantly increased sensitivity to cisplatin in ovarian carcinoma cells. Conclusion: We conclude that CCL11 signaling plays an important role in proliferation and invasion of ovarian carcinoma cells and CCL11 pathway could be targeted for therapy in ovarian cancer. Furthermore, CCL11 could be used as a biomarker and a prognostic factor of relapse-free survival in ovarian cancer. © 2009 American Association for Cancer Research.

Authors
Levina, V; Nolen, BM; Marrangoni, AM; Cheng, P; Marks, JR; Szczepanski, MJ; Szajnik, ME; Gorelik, E; Lokshin, AE
MLA Citation
Levina, V, Nolen, BM, Marrangoni, AM, Cheng, P, Marks, JR, Szczepanski, MJ, Szajnik, ME, Gorelik, E, and Lokshin, AE. "Role of eotaxin-1 signaling in ovarian cancer." Clinical Cancer Research 15.8 (2009): 2647-2656.
PMID
19351767
Source
scival
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
8
Publish Date
2009
Start Page
2647
End Page
2656
DOI
10.1158/1078-0432.CCR-08-2024

A clinicogenomic model to predict lymph node metastasis in breast cancer

Authors
Danko, ME; Untch, BR; Tebbit, CL; Zhai, J; Dressman, HK; Bentley, RC; Baker, J; Marks, JR; Nevins, JR; Jr, OJA
MLA Citation
Danko, ME, Untch, BR, Tebbit, CL, Zhai, J, Dressman, HK, Bentley, RC, Baker, J, Marks, JR, Nevins, JR, and Jr, OJA. "A clinicogenomic model to predict lymph node metastasis in breast cancer." September 2008.
Source
wos-lite
Published In
Journal of The American College of Surgeons
Volume
207
Issue
3
Publish Date
2008
Start Page
S45
End Page
S45
DOI
10.1016/j.jamcollsurg.2008.06.092

Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression.

PURPOSE: Breast cancer arising in young women is correlated with inferior survival and higher incidence of negative clinicopathologic features. The biology driving this aggressive disease has yet to be defined. PATIENTS AND METHODS: Clinically annotated, microarray data from 784 early-stage breast cancers were identified, and prospectively defined, age-specific cohorts (young: /= 65 years, n = 211) were compared by prognosis, clinicopathologic variables, mRNA expression values, single-gene analysis, and gene set enrichment analysis (GSEA). Univariate and multivariate analyses were performed. RESULTS: Using clinicopathologic variables, young women illustrated lower estrogen receptor (ER) positivity (immunohistochemistry [IHC], P = .027), larger tumors (P = .012), higher human epidermal growth factor receptor 2 (HER-2) overexpression (IHC, P = .075), lymph node positivity (P = .008), higher grade tumors (P < .0001), and trends toward inferior disease-free survival (DFS; hazard ratio = 1.32; P = .094). Using genomic expression analysis, tumors arising in young women had significantly lower ERalpha mRNA (P < .0001), ERbeta (P = .02), and progesterone receptor (PR) expression (P < .0001), but higher HER-2 (P < .0001) and epidermal growth factor receptor (EGFR) expression (P < .0001). Exploratory analysis (GSEA) revealed 367 biologically relevant gene sets significantly distinguishing breast tumors arising in young women. Combining clinicopathologic and genomic variables among tumors arising in young women demonstrated that younger age and lower ERbeta and higher EGFR mRNA expression were significant predictors of inferior DFS. CONCLUSION: This large-scale genomic analysis illustrates that breast cancer arising in young women is a unique biologic entity driven by unifying oncogenic signaling pathways, is characterized by less hormone sensitivity and higher HER-2/EGFR expression, and warrants further study to offer this poor-prognosis group of women better preventative and therapeutic options.

Authors
Anders, CK; Hsu, DS; Broadwater, G; Acharya, CR; Foekens, JA; Zhang, Y; Wang, Y; Marcom, PK; Marks, JR; Febbo, PG; Nevins, JR; Potti, A; Blackwell, KL
MLA Citation
Anders, CK, Hsu, DS, Broadwater, G, Acharya, CR, Foekens, JA, Zhang, Y, Wang, Y, Marcom, PK, Marks, JR, Febbo, PG, Nevins, JR, Potti, A, and Blackwell, KL. "Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression." J Clin Oncol 26.20 (July 10, 2008): 3324-3330.
PMID
18612148
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
20
Publish Date
2008
Start Page
3324
End Page
3330
DOI
10.1200/JCO.2007.14.2471

Cyclin E overexpression in epithelial ovarian cancer characterizes an etiologic subgroup.

BACKGROUND: The objective of this study was to determine whether cyclin E overexpression defines an etiologically distinct subgroup of ovarian cancer. METHODS: We analyzed data from 538 epithelial ovarian cancer cases and 629 controls enrolled in a population-based case-control study. Cyclin E protein overexpression was assessed using immunohistochemistry. Case-control and case-case comparisons were done to evaluate the relationship between cyclin E overexpression and epidemiologic risk factors. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) while adjusting for potential confounders. RESULTS: Case-control comparisons showed ovarian cancers with and without cyclin E overexpression have different associations with several epidemiologic risk factors. A dose-response relationship was observed between lifetime ovulatory cycles (LOC) and ovarian cancer that overexpressed cyclin E [OR, 1.8; 95% CI, 1.1-3.0 for moderately high LOC (265-390 cycles) and OR, 2.7; 95% CI, 1.6-4.5 for high LOC (>390 cycles) compared with low LOC (<265 cycles)], but no relationship was seen with cancers that lacked overexpression. The most important components of the LOC variable contributing to the differences in the association with the cyclin E subgroups of ovarian cancer were months of oral contraceptive use and months pregnant. CONCLUSIONS: Cyclin E overexpression is associated with a high number of LOC, largely influenced by oral contraceptive use and pregnancy. This suggests that cyclin E overexpression is a molecular signature characteristic of ovarian cancer cases that may arise via a pathway that involves ovulation-induced alterations.

Authors
Schildkraut, JM; Moorman, PG; Bland, AE; Halabi, S; Calingaert, B; Whitaker, R; Lee, PS; Elkins-Williams, T; Bentley, RC; Marks, JR; Berchuck, A
MLA Citation
Schildkraut, JM, Moorman, PG, Bland, AE, Halabi, S, Calingaert, B, Whitaker, R, Lee, PS, Elkins-Williams, T, Bentley, RC, Marks, JR, and Berchuck, A. "Cyclin E overexpression in epithelial ovarian cancer characterizes an etiologic subgroup." Cancer Epidemiol Biomarkers Prev 17.3 (March 2008): 585-593.
PMID
18349276
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
17
Issue
3
Publish Date
2008
Start Page
585
End Page
593
DOI
10.1158/1055-9965.EPI-07-0596

Stem cell marker CD133 (PROMININ-1) is epigenetically regulated in ovarian cancer

Authors
Baba, T; Convery, PA; Matsumura, N; Whitaker, RS; Perry, T; Huang, Z; Mori, S; Kondoh, E; Bentley, RC; Fujii, S; Marks, JR; Berchuck, A; Murphy, SK
MLA Citation
Baba, T, Convery, PA, Matsumura, N, Whitaker, RS, Perry, T, Huang, Z, Mori, S, Kondoh, E, Bentley, RC, Fujii, S, Marks, JR, Berchuck, A, and Murphy, SK. "Stem cell marker CD133 (PROMININ-1) is epigenetically regulated in ovarian cancer." March 2008.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
108
Issue
3
Publish Date
2008
Start Page
S104
End Page
S104

Yeast screens identify the RNA polymerase II CTD and SPT5 as relevant targets of BRCA1 interaction.

BRCA1 has been implicated in numerous DNA repair pathways that maintain genome integrity, however the function responsible for its tumor suppressor activity in breast cancer remains obscure. To identify the most highly conserved of the many BRCA1 functions, we screened the evolutionarily distant eukaryote Saccharomyces cerevisiae for mutants that suppressed the G1 checkpoint arrest and lethality induced following heterologous BRCA1 expression. A genome-wide screen in the diploid deletion collection combined with a screen of ionizing radiation sensitive gene deletions identified mutants that permit growth in the presence of BRCA1. These genes delineate a metabolic mRNA pathway that temporally links transcription elongation (SPT4, SPT5, CTK1, DEF1) to nucleopore-mediated mRNA export (ASM4, MLP1, MLP2, NUP2, NUP53, NUP120, NUP133, NUP170, NUP188, POM34) and cytoplasmic mRNA decay at P-bodies (CCR4, DHH1). Strikingly, BRCA1 interacted with the phosphorylated RNA polymerase II (RNAPII) carboxy terminal domain (P-CTD), phosphorylated in the pattern specified by the CTDK-I kinase, to induce DEF1-dependent cleavage and accumulation of a RNAPII fragment containing the P-CTD. Significantly, breast cancer associated BRCT domain defects in BRCA1 that suppressed P-CTD cleavage and lethality in yeast also suppressed the physical interaction of BRCA1 with human SPT5 in breast epithelial cells, thus confirming SPT5 as a relevant target of BRCA1 interaction. Furthermore, enhanced P-CTD cleavage was observed in both yeast and human breast cells following UV-irradiation indicating a conserved eukaryotic damage response. Moreover, P-CTD cleavage in breast epithelial cells was BRCA1-dependent since damage-induced P-CTD cleavage was only observed in the mutant BRCA1 cell line HCC1937 following ectopic expression of wild type BRCA1. Finally, BRCA1, SPT5 and hyperphosphorylated RPB1 form a complex that was rapidly degraded following MMS treatment in wild type but not BRCA1 mutant breast cells. These results extend the mechanistic links between BRCA1 and transcriptional consequences in response to DNA damage and suggest an important role for RNAPII P-CTD cleavage in BRCA1-mediated cancer suppression.

Authors
Bennett, CB; Westmoreland, TJ; Verrier, CS; Blanchette, CAB; Sabin, TL; Phatnani, HP; Mishina, YV; Huper, G; Selim, AL; Madison, ER; Bailey, DD; Falae, AI; Galli, A; Olson, JA; Greenleaf, AL; Marks, JR
MLA Citation
Bennett, CB, Westmoreland, TJ, Verrier, CS, Blanchette, CAB, Sabin, TL, Phatnani, HP, Mishina, YV, Huper, G, Selim, AL, Madison, ER, Bailey, DD, Falae, AI, Galli, A, Olson, JA, Greenleaf, AL, and Marks, JR. "Yeast screens identify the RNA polymerase II CTD and SPT5 as relevant targets of BRCA1 interaction. (Published online)" PLoS One 3.1 (January 16, 2008): e1448-.
Website
http://hdl.handle.net/10161/4482
PMID
18197258
Source
pubmed
Published In
PloS one
Volume
3
Issue
1
Publish Date
2008
Start Page
e1448
DOI
10.1371/journal.pone.0001448

Age-specific differences in oncogenic pathway deregulation seen in human breast tumors.

PURPOSE: To define the biology driving the aggressive nature of breast cancer arising in young women. EXPERIMENTAL DESIGN: Among 784 patients with early stage breast cancer, using prospectively-defined, age-specific cohorts (young or=65 years), 411 eligible patients (n = 200or=65 years) with clinically-annotated Affymetrix microarray data were identified. GSEA, signatures of oncogenic pathway deregulation and predictors of chemotherapy sensitivity were evaluated within the two age-defined cohorts. RESULTS: In comparing deregulation of oncogenic pathways between age groups, a higher probability of PI3K (p = 0.006) and Myc (p = 0.03) pathway deregulation was observed in breast tumors arising in younger women. When evaluating unique patterns of pathway deregulation, a low probability of Src and E2F deregulation in tumors of younger women, concurrent with a higher probability of PI3K, Myc, and beta-catenin, conferred a worse prognosis (HR = 4.15). In contrast, a higher probability of Src and E2F pathway activation in tumors of older women, with concurrent low probability of PI3K, Myc and beta-catenin deregulation, was associated with poorer outcome (HR = 2.7). In multivariate analyses, genomic clusters of pathway deregulation illustrate prognostic value. CONCLUSION: Results demonstrate that breast cancer arising in young women represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that are prognostic, independent of currently available clinico-pathologic variables. These results should enable refinement of targeted treatment strategies in this clinically challenging situation.

Authors
Anders, CK; Acharya, CR; Hsu, DS; Broadwater, G; Garman, K; Foekens, JA; Zhang, Y; Wang, Y; Marcom, K; Marks, JR; Mukherjee, S; Nevins, JR; Blackwell, KL; Potti, A
MLA Citation
Anders, CK, Acharya, CR, Hsu, DS, Broadwater, G, Garman, K, Foekens, JA, Zhang, Y, Wang, Y, Marcom, K, Marks, JR, Mukherjee, S, Nevins, JR, Blackwell, KL, and Potti, A. "Age-specific differences in oncogenic pathway deregulation seen in human breast tumors. (Published online)" PLoS One 3.1 (January 2, 2008): e1373-.
Website
http://hdl.handle.net/10161/4481
PMID
18167534
Source
pubmed
Published In
PloS one
Volume
3
Issue
1
Publish Date
2008
Start Page
e1373
DOI
10.1371/journal.pone.0001373

Corrigendum: Genomic signatures to guide the use of chemotherapeutics (Nature Medicine (2006) 12, (1294-1300))

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, RF, Chan, G, Sayer, R, Cragun, J, Cottrill, H, Kelley, MJ, Petersen, R, Harpole, D, Marks, J, Berchuck, A, Ginsburg, GS, Febbo, P, Lancaster, J, and Nevins, JR. "Corrigendum: Genomic signatures to guide the use of chemotherapeutics (Nature Medicine (2006) 12, (1294-1300))." Nature Medicine 14.8 (2008): 889--.
Source
scival
Published In
Nature Medicine
Volume
14
Issue
8
Publish Date
2008
Start Page
889-
DOI
10.1038/nm0808-889

Serum biomarker profiles and response to neoadjuvant chemotherapy for locally advanced breast cancer

Introduction: Neoadjuvant chemotherapy has become the standard of care for the diverse population of women diagnosed with locally advanced breast cancer. Serum biomarker levels are increasingly being investigated for their ability to predict therapy response and aid in the development of individualized treatment regimens. Multianalyte profiles may offer greater predictive power for neoadjuvant treatment response than the individual biomarkers currently in use.Methods: Serum samples were collected from 44 patients enrolled in a phase I-II, open-label study of liposomal doxorubicin and paclitaxel in combination with whole breast hyperthermia for the neoadjuvant treatment of locally advanced breast cancer (stage IIB or stage III). Samples were collected prior to each of four rounds of treatment and prior to definitive surgery. Samples were assayed by Luminex assay for 55 serum biomarkers, including cancer antigens, growth/angiogenic factors, apoptosis-related molecules, metastasis-related molecules, adhesion molecules, adipokines, cytokines, chemokines, hormones, and other proteins.Results: Biomarker levels were compared retrospectively with clinical and pathologic treatment responses. Univariate analysis of the data identified several groups of biomarkers that differed significantly among treatment outcome groups early in the course of neoadjuvant chemotherapy. Multivariate statistical analysis revealed multibiomarker panels that could differentiate between treatment response groups with high sensitivity and specificity.Conclusion: We demonstrate here that serum biomarker profiles may offer predictive power concerning treatment response and outcome in the neoadjuvant setting. The continued development of these findings will be of considerable clinical utility in the design of treatment regimens for individual breast cancer patients. © 2008 Nolen et al.; licensee BioMed Central Ltd.

Authors
Nolen, BM; Marks, JR; Ta'san, S; Rand, A; Luong, TM; Wang, Y; Blackwell, K; Lokshin, AE
MLA Citation
Nolen, BM, Marks, JR, Ta'san, S, Rand, A, Luong, TM, Wang, Y, Blackwell, K, and Lokshin, AE. "Serum biomarker profiles and response to neoadjuvant chemotherapy for locally advanced breast cancer." Breast Cancer Research 10.3 (2008).
PMID
18474099
Source
scival
Published In
Breast Cancer Research
Volume
10
Issue
3
Publish Date
2008
DOI
10.1186/bcr2096

ISG15 as a novel tumor biomarker for drug sensitivity

Tumor cells are known to exhibit highly varied sensitivity to camptothecins (CPT; e.g., irinotecan and topotecan). However, the factors that determine CPT sensitivity/ resistance are largely unknown. Recent studies have shown that the ubiquitin-like protein, IFN-stimulated gene 15 (ISG15), which is highly elevated in many human cancers and tumor cell lines, antagonizes the ubiquitin/ proteasome pathway. In the present study, we show that ISG15 is a determinant for CPT sensitivity/resistance possibly through its effect on proteasome-mediated repair of topoisomerase I (TOP1)-DNA covalent complexes. First, short hairpin RNA-mediated knockdown of either ISG15 or UbcH8 (major E2 for ISG15) in breast cancer ZR-75-1 cells decreased CPT sensitivity, suggesting that ISG15 overexpression in tumors could be a factor affecting intrinsic CPT sensitivity in tumor cells. Second, the level of ISG15 was found to be significantly reduced in several tumor cells selected for resistance to CPT, suggesting that altered ISG15 regulation could be a significant determinant for acquired CPT resistance. Parallel to reduced CPT sensitivity, short hairpin RNAmediated knockdown of either ISG15 or UbcH8 in ZR-75-1 cells resulted in increased proteasomal degradation of CPT-induced TOP1-DNA covalent complexes. Taken together, these results suggest that ISG15, which interferes with proteasome-mediated repair of TOP1-DNA covalent complexes, is a potential tumor biomarker for CPT sensitivity. Copyright © 2008 American Association for Cancer Research.

Authors
Desai, SD; Wood, LM; Tsai, Y-C; Hsieh, T-S; Marks, JR; Scott, GL; Giovanella, BC; Liu, LF
MLA Citation
Desai, SD, Wood, LM, Tsai, Y-C, Hsieh, T-S, Marks, JR, Scott, GL, Giovanella, BC, and Liu, LF. "ISG15 as a novel tumor biomarker for drug sensitivity." Molecular Cancer Therapeutics 7.6 (2008): 1430-1439.
PMID
18566215
Source
scival
Published In
Molecular cancer therapeutics
Volume
7
Issue
6
Publish Date
2008
Start Page
1430
End Page
1439
DOI
10.1158/1535-7163.MCT-07-2345

Stem cell marker CD133 (PROMININ-1) is epigenetically regulated in ovarian cancer

Authors
Baba, T; Convey, P; Matsumura, N; Whitaker, RS; Perry, T; Huang, Z; Mori, S; Kondoh, E; Bentley, RC; Fujii, S; Berchuck, A; Murphy, SK; Marks, JR
MLA Citation
Baba, T, Convey, P, Matsumura, N, Whitaker, RS, Perry, T, Huang, Z, Mori, S, Kondoh, E, Bentley, RC, Fujii, S, Berchuck, A, Murphy, SK, and Marks, JR. "Stem cell marker CD133 (PROMININ-1) is epigenetically regulated in ovarian cancer." 2008.
Source
wos-lite
Published In
Cancer biomarkers : section A of Disease markers
Volume
4
Issue
3
Publish Date
2008
Start Page
175
End Page
176

Grade-specific prostate cancer associations of IGF1 (CA)19 repeats and IGFBP3-202A/C in blacks and whites.

Carrying the cytosine-adenosine (CA)19 repeat polymorphism in insulin-like growth factor-1 (IGF1) is associated with lower serum proteins and decreased prostate cancer risk. Carrying the -202A/C genotype in insulin-like growth factor binding protein-3 (IGFBP3) also has been associated with lower serum levels of the binding protein. However, the association between this variant and prostate cancer is inconsistent. To test the hypothesis that inconsistencies are partly due to cancer grade-specific differences in strength and direction of associations, we reanalyzed data from our previous Durham Veterans Administration Hospital study of blacks and whites comprising 47 cases (19 African Americans) with Gleason sum > or = 7, 50 cases (30 African Americans) with Gleason sum < 7 and 93 controls (49 African Americans). Compared to controls, the association between carrying the IGFBP3 C allele and prostate cancer risk was in OR(Low-Gleason) = 4.0; 95% CI: 1.4-12.3 compared to OR(High-Gleason) = 1.0; 95% CI: 0.4-2.2. Association patterns were similar in African Americans (OR(Low-Gleason) = 3.6; 95% CI: 1.0-13.2 vs. OR(High-Gleason) = 1.4; 95% CI: 0.4-2.3) and whites (OR(Low-Gleason) = 5.6; 95% CI: 0.6-49.0 vs. OR(High-Gleason) = 0.6; 95% CI: 0.2-2.2). The inverse association between carrying the IGF1 (CA)19 repeat variant did not vary by grade or ethnicity. If confirmed in larger studies, these findings support the hypothesis that the association between IGFBP3 C allele and prostate cancer is grade specific in both ethnic groups.

Authors
Hoyo, C; Grubber, J; Demark-Wahnefried, W; Marks, JR; Freedland, SJ; Jeffreys, AS; Grambow, SC; Wenham, RM; Walther, PJ; Schildkraut, JM
MLA Citation
Hoyo, C, Grubber, J, Demark-Wahnefried, W, Marks, JR, Freedland, SJ, Jeffreys, AS, Grambow, SC, Wenham, RM, Walther, PJ, and Schildkraut, JM. "Grade-specific prostate cancer associations of IGF1 (CA)19 repeats and IGFBP3-202A/C in blacks and whites." J Natl Med Assoc 99.7 (July 2007): 718-722.
PMID
17668637
Source
pubmed
Published In
Journal of the National Medical Association
Volume
99
Issue
7
Publish Date
2007
Start Page
718
End Page
722

Regulation of the metastasis suppressor gene MKK4 in ovarian cancer.

OBJECTIVES: MKK4 is a metastasis suppressor that is downregulated in some ovarian cancers. We sought to investigate whether promoter methylation, loss of heterozygosity, or changes in phosphorylation are involved in MKK4 dysregulation during ovarian carcinogenesis. METHODS: Bisulfite sequencing was used to determine MKK4 promoter methylation. PCR analysis of tumor/normal DNA was performed to determine LOH at the MKK4 locus. Normal human ovarian surface epithelium (HOSE) and SKOV-3 cells were serum starved and treated with EGF, TGFbeta, or wortmannin. Western blotting was performed using antibodies that detect total and phosphorylated MKK4. RESULTS: No MKK4 promoter hypermethylation was detected in 21 ovarian cancers. LOH was detected at the MKK4 intragenic marker D17S969 in 35% of cases and at D17S1303 in 20%. MKK4 protein was detected in 97% of ovarian tumors. The inactivated phosphoserine 80 (ser-80) form comprised 62% of phosphorylated MKK4 protein in ovarian tumors. Treatment of HOSE or SKOV-3 cells with EGF induced a 1.7- to 4.2-fold increase in phosphorylation of ser-80 MKK4 without altering total MKK4 protein. TGFbeta increased MKK4 ser-80 phosphorylation by 5.4-fold above baseline. The PI3K/Akt pathway inhibitor wortmannin decreased the amount of ser-80 MKK4 by 50%, and inhibited EGF stimulation of MKK4 ser-80 phosphorylation by 60%. CONCLUSIONS: LOH of MKK4 occurs in some ovarian cancers, but without loss of MKK4 protein. MKK4 expression does not appear to be downregulated by promoter methylation. Peptide growth factors induce MKK4 ser-80 phosphorylation, which downregulates its activity. PI3K/Akt pathway inhibitors can partially block ser-80 phosphorylation and this may have therapeutic implications.

Authors
Spillman, MA; Lacy, J; Murphy, SK; Whitaker, RS; Grace, L; Teaberry, V; Marks, JR; Berchuck, A
MLA Citation
Spillman, MA, Lacy, J, Murphy, SK, Whitaker, RS, Grace, L, Teaberry, V, Marks, JR, and Berchuck, A. "Regulation of the metastasis suppressor gene MKK4 in ovarian cancer." Gynecol Oncol 105.2 (May 2007): 312-320.
PMID
17276500
Source
pubmed
Published In
Gynecologic Oncology
Volume
105
Issue
2
Publish Date
2007
Start Page
312
End Page
320
DOI
10.1016/j.ygyno.2006.12.017

Tagging single nucleotide polymorphisms in cell cycle control genes and susceptibility to invasive epithelial ovarian cancer.

High-risk susceptibility genes explain <40% of the excess risk of familial ovarian cancer. Therefore, other ovarian cancer susceptibility genes are likely to exist. We have used a single nucleotide polymorphism (SNP)-tagging approach to evaluate common variants in 13 genes involved in cell cycle control-CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, and CDKN2D-and risk of invasive epithelial ovarian cancer. We used a two-stage, multicenter, case-control study. In stage 1, 88 SNPs that tag common variation in these genes were genotyped in three studies from the United Kingdom, United States, and Denmark ( approximately 1,500 cases and 2,500 controls). Genotype frequencies in cases and controls were compared using logistic regression. In stage 2, eight other studies from Australia, Poland, and the United States ( approximately 2,000 cases and approximately 3,200 controls) were genotyped for the five most significant SNPs from stage 1. No SNP was significant in the stage 2 data alone. Using the combined stages 1 and 2 data set, CDKN2A rs3731257 and CDKN1B rs2066827 were associated with disease risk (unadjusted P trend = 0.008 and 0.036, respectively), but these were not significant after adjusting for multiple testing. Carrying the minor allele of these SNPs was found to be associated with reduced risk [OR, 0.91 (0.85-0.98) for rs3731257; and OR, 0.93 (0.87-0.995) for rs2066827]. In conclusion, we have found evidence that a single tagged SNP in both the CDKN2A and CDKN1B genes may be associated with reduced ovarian cancer risk. This study highlights the need for multicenter collaborations for genetic association studies.

Authors
Gayther, SA; Song, H; Ramus, SJ; Kjaer, SK; Whittemore, AS; Quaye, L; Tyrer, J; Shadforth, D; Hogdall, E; Hogdall, C; Blaeker, J; DiCioccio, R; McGuire, V; Webb, PM; Beesley, J; Green, AC; Whiteman, DC; Australian Ovarian Cancer Study Group, ; Goodman, MT; Lurie, G; Carney, ME; Modugno, F; Ness, RB; Edwards, RP; Moysich, KB; Goode, EL; Couch, FJ; Cunningham, JM; Sellers, TA; Wu, AH; Pike, MC; Iversen, ES; Marks, JR; Garcia-Closas, M; Brinton, L; Lissowska, J; Peplonska, B; Easton, DF; Jacobs, I et al.
MLA Citation
Gayther, SA, Song, H, Ramus, SJ, Kjaer, SK, Whittemore, AS, Quaye, L, Tyrer, J, Shadforth, D, Hogdall, E, Hogdall, C, Blaeker, J, DiCioccio, R, McGuire, V, Webb, PM, Beesley, J, Green, AC, Whiteman, DC, Australian Ovarian Cancer Study Group, , Goodman, MT, Lurie, G, Carney, ME, Modugno, F, Ness, RB, Edwards, RP, Moysich, KB, Goode, EL, Couch, FJ, Cunningham, JM, Sellers, TA, Wu, AH, Pike, MC, Iversen, ES, Marks, JR, Garcia-Closas, M, Brinton, L, Lissowska, J, Peplonska, B, Easton, DF, and Jacobs, I et al. "Tagging single nucleotide polymorphisms in cell cycle control genes and susceptibility to invasive epithelial ovarian cancer." Cancer Res 67.7 (April 1, 2007): 3027-3035.
PMID
17409409
Source
pubmed
Published In
Cancer Research
Volume
67
Issue
7
Publish Date
2007
Start Page
3027
End Page
3035
DOI
10.1158/0008-5472.CAN-06-3261

Isogenic normal basal and luminal mammary epithelial isolated by a novel method show a differential response to ionizing radiation.

Epithelial cells within the normal breast duct seem to be the primary target for neoplastic transformation events that eventually produce breast cancer. Normal epithelial cells are easily isolated and propagated using standard techniques. However, these techniques almost invariably result in populations of cells that are largely basal in character. Because only approximately 20% of human breast cancers exhibit a basal phenotype, our understanding of the disease may be skewed by using these cells as the primary comparator to cancer. Further, because germ line mutations in BRCA1 yield breast cancers that are most often of the basal type, a comparison of normal basal and luminal cells could yield insight into the tissue and cell type specificity of this hereditary cancer susceptibility gene. In this report, we describe a simplified and efficient method for isolating basal and luminal cells from normal human breast tissue. These isogenic cells can be independently propagated and maintain phenotypic markers consistent with their respective lineages. Using these cultured cells, we show that basal and luminal cells exhibit distinct responses to ionizing radiation. Basal cells undergo a rapid but labile cell cycle arrest, whereas luminal cells show a much more durable arrest, primarily at the G(2)-M boundary. Molecular markers, including p53 protein accumulation, p53-activated genes, and BRCA1 nuclear focus formation all correlate with the respective cell cycle responses. Further, we show that short-term cultures of human breast tissue fragments treated with ionizing radiation show a similar phenomenon as indicated by the biphasic accumulation of p53 protein in the basal versus luminal layer. Together, these results indicate that normal basal cells have a transitory cell cycle arrest after DNA damage that may underlie their increased susceptibility to transformation after the loss of functional BRCA1.

Authors
Huper, G; Marks, JR
MLA Citation
Huper, G, and Marks, JR. "Isogenic normal basal and luminal mammary epithelial isolated by a novel method show a differential response to ionizing radiation." Cancer Res 67.7 (April 1, 2007): 2990-3001.
PMID
17409405
Source
pubmed
Published In
Cancer Research
Volume
67
Issue
7
Publish Date
2007
Start Page
2990
End Page
3001
DOI
10.1158/0008-5472.CAN-06-4065

Trinucleotide repeat polymorphisms in the androgen receptor gene and risk of ovarian cancer.

INTRODUCTION: Androgens may play a role in the development of ovarian cancers. Two trinucleotide repeat polymorphisms have been described in exon 1 of the androgen receptor (AR) gene that may affect its function. Previous studies of ovarian cancer and AR repeat polymorphisms have been inconsistent. METHODS: We analyzed CAG and GGC repeat length polymorphisms in the AR gene using data from a population-based case-control study of ovarian cancer that included 594 cases and 681 controls. Repeat lengths were determined by fluorescent DNA fragment analysis using ABI GeneScan software. Change point models were used to determine appropriate repeat length cutoff points by race (African American versus Caucasian) for both the shorter and longer CAG and GGC repeats. RESULTS: No relationship was observed between CAG repeat length and ovarian cancer among Caucasians. Among African Americans, having a short repeat length on either allele was associated with a 2-fold increase in ovarian cancer risk (age-adjusted odds ratio, 2.2; 95% confidence interval, 1.1-4.1). Having short CAG repeat lengths for both alleles was associated with a 5-fold increased risk for developing ovarian cancer (age-adjusted odds ratio, 5.4; 95% confidence interval, 1.4-1.7). No relationship with the GGC repeat length polymorphisms was observed. CONCLUSION: These results suggest that having a short CAG repeat length in AR increases ovarian cancer risk in African Americans. The failure to observe this relationship in Caucasians may be due to the rarity of such short CAG alleles in this population or could reflect racial differences in disease etiology.

Authors
Schildkraut, JM; Murphy, SK; Palmieri, RT; Iversen, E; Moorman, PG; Huang, Z; Halabi, S; Calingaert, B; Gusberg, A; Marks, JR; Berchuck, A
MLA Citation
Schildkraut, JM, Murphy, SK, Palmieri, RT, Iversen, E, Moorman, PG, Huang, Z, Halabi, S, Calingaert, B, Gusberg, A, Marks, JR, and Berchuck, A. "Trinucleotide repeat polymorphisms in the androgen receptor gene and risk of ovarian cancer." Cancer Epidemiol Biomarkers Prev 16.3 (March 2007): 473-480.
PMID
17372242
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
16
Issue
3
Publish Date
2007
Start Page
473
End Page
480
DOI
10.1158/1055-9965.EPI-06-0868

Most early-stage serous ovarian cancers have gene expression profiles predictive of long-term survival

Authors
Berchuck, A; Lancaster, JM; Iversen, ES; Luo, J; Levine, DA; Boyd, J; Secord, AA; Marks, JR; Nevins, JR; Dressman, H
MLA Citation
Berchuck, A, Lancaster, JM, Iversen, ES, Luo, J, Levine, DA, Boyd, J, Secord, AA, Marks, JR, Nevins, JR, and Dressman, H. "Most early-stage serous ovarian cancers have gene expression profiles predictive of long-term survival." March 2007.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
104
Issue
3
Publish Date
2007
Start Page
S15
End Page
S16

An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer.

PURPOSE: The purpose of this study was to develop an integrated genomic-based approach to personalized treatment of patients with advanced-stage ovarian cancer. We have used gene expression profiles to identify patients likely to be resistant to primary platinum-based chemotherapy and also to identify alternate targeted therapeutic options for patients with de novo platinum-resistant disease. PATIENTS AND METHODS: A gene expression model that predicts response to platinum-based therapy was developed using a training set of 83 advanced-stage serous ovarian cancers and tested on a 36-sample external validation set. In parallel, expression signatures that define the status of oncogenic signaling pathways were evaluated in 119 primary ovarian cancers and 12 ovarian cancer cell lines. In an effort to increase chemotherapy sensitivity, pathways shown to be activated in platinum-resistant cancers were subject to targeted therapy in ovarian cancer cell lines. RESULTS: Gene expression profiles identified patients with ovarian cancer likely to be resistant to primary platinum-based chemotherapy with greater than 80% accuracy. In patients with platinum-resistant disease, we identified expression signatures consistent with activation of Src and Rb/E2F pathways, components of which were successfully targeted to increase response in ovarian cancer cell lines. CONCLUSION: We have defined a strategy for treatment of patients with advanced-stage ovarian cancer that uses therapeutic stratification based on predictions of response to chemotherapy, coupled with prediction of oncogenic pathway deregulation, as a method to direct the use of targeted agents.

Authors
Dressman, HK; Berchuck, A; Chan, G; Zhai, J; Bild, A; Sayer, R; Cragun, J; Clarke, J; Whitaker, RS; Li, L; Gray, J; Marks, J; Ginsburg, GS; Potti, A; West, M; Nevins, JR; Lancaster, JM
MLA Citation
Dressman, HK, Berchuck, A, Chan, G, Zhai, J, Bild, A, Sayer, R, Cragun, J, Clarke, J, Whitaker, RS, Li, L, Gray, J, Marks, J, Ginsburg, GS, Potti, A, West, M, Nevins, JR, and Lancaster, JM. "An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer." J Clin Oncol 25.5 (February 10, 2007): 517-525.
PMID
17290060
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
5
Publish Date
2007
Start Page
517
End Page
525
DOI
10.1200/JCO.2006.06.3743

The type III TGF-beta receptor suppresses breast cancer progression.

The TGF-beta signaling pathway has a complex role in regulating mammary carcinogenesis. Here we demonstrate that the type III TGF-beta receptor (TbetaRIII, or betaglycan), a ubiquitously expressed TGF-beta coreceptor, regulated breast cancer progression and metastasis. Most human breast cancers lost TbetaRIII expression, with loss of heterozygosity of the TGFBR3 gene locus correlating with decreased TbetaRIII expression. TbetaRIII expression decreased during breast cancer progression, and low TbetaRIII levels predicted decreased recurrence-free survival in breast cancer patients. Restoring TbetaRIII expression in breast cancer cells dramatically inhibited tumor invasiveness in vitro and tumor invasion, angiogenesis, and metastasis in vivo. TbetaRIII appeared to inhibit tumor invasion by undergoing ectodomain shedding and producing soluble TbetaRIII, which binds and sequesters TGF-beta to decrease TGF-beta signaling and reduce breast cancer cell invasion and tumor-induced angiogenesis. Our results indicate that loss of TbetaRIII through allelic imbalance is a frequent genetic event during human breast cancer development that increases metastatic potential.

Authors
Dong, M; How, T; Kirkbride, KC; Gordon, KJ; Lee, JD; Hempel, N; Kelly, P; Moeller, BJ; Marks, JR; Blobe, GC
MLA Citation
Dong, M, How, T, Kirkbride, KC, Gordon, KJ, Lee, JD, Hempel, N, Kelly, P, Moeller, BJ, Marks, JR, and Blobe, GC. "The type III TGF-beta receptor suppresses breast cancer progression." J Clin Invest 117.1 (January 2007): 206-217.
PMID
17160136
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
117
Issue
1
Publish Date
2007
Start Page
206
End Page
217
DOI
10.1172/JCI29293

Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature (2006) 12, (1294-1300))

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, RF, Chan, G, Sayer, R, Cragun, J, Cottrill, H, Kelley, MJ, Petersen, R, Harpole, D, Marks, J, Berchuck, A, Ginsburg, GS, Febbo, P, Lancaster, J, and Nevins, JR. "Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature (2006) 12, (1294-1300))." Nature Medicine 13.11 (2007): 1388--.
Source
scival
Published In
Nature Medicine
Volume
13
Issue
11
Publish Date
2007
Start Page
1388-
DOI
10.1038/nm1107-1388

Decision fusion of circulating markers for breast cancer detection in premenopausal women

Current mammographic screeningfor breast cancer is less effective for younger women. To complement mammography for premenopausal women, we investigated the feasibility screening test using 98 blood serum proteins. Because the data set was very noisy and contained only weak features, we used a classifier designed for noisy data: decision fusion. Decision fusion outperformed both a support vector machine (SVM) and linear regression with forward stepwise feature selection on all three two-class classification tasks: normal tissue vs. cancer, normal tissue vs. benign lesions, and benign lesions vs. cancer. Decision fusion detected cancer moderately well (AUC=0.84 on normal vs. cancer), demonstrating promise as a screening tool. Decision fusion also detected benign lesions similarly well (AUC=0.83 on normal vs. benign lesions) and was the only classifier to achieve any success in separating benign from malignant lesions (AUC=0.64 on benign vs. cancer). The classification results suggest that the assayed proteins are more indicative of a secondary effect, such as immune response, rather than specific for breast cancer. In conclusion, the decision fusion classifier demonstrated some promise in detecting breast lesions and outperformed other classifiers, especially for the very noisy classification problem of distinguishing benign from malignant lesions. ©2007 IEEE.

Authors
Jesneck, JL; Mukherjee, S; Nolte, LW; Lokshin, AE; Marks, JR; Lo, J
MLA Citation
Jesneck, JL, Mukherjee, S, Nolte, LW, Lokshin, AE, Marks, JR, and Lo, J. "Decision fusion of circulating markers for breast cancer detection in premenopausal women." 2007. 1434-1438.
Source
scival
Publish Date
2007
Start Page
1434
End Page
1438
DOI
10.1109/BIBE.2007.4375762

Pooling of case specimens to create standard serum sets for screening cancer biomarkers

Background: Multiple identical sets of sera from cancer cases and controls would facilitate standardized testing of biomarkers. We describe the creation and use of standard serum sets developed from healthy donors and pooled sera from ovarian, breast, and endometrial cancer cases. Methods: Two hundred seventy-five 0.3-mL aliquots of sera were created for each of the 95 healthy women, and residual serum was pooled to create 275 identical sets of 20 0.3-mL aliquots. Aliquots (1.0-1.5 mL) from 441 women were combined to create 12 breast and pelvic disease pools with at least 115 0.3-mL aliquots. Sets were assembled to contain aliquots from individual controls, replicates, and disease pools. Cancer antigens (CA), CA 125, CA 19.9, and CA 15.3, and carcinoembryonic antigen were measured in one set and in 217 women comprising six of the pelvic disease pools. Use of a set was illustrated for mesothelin (soluble mesothelin-related protein). Statistical output included concentration differences between pooled cases and controls (z values for single analytes; Mahalanobis distances for pairs), correlation between z values and sensitivities, coefficient of variations, and standardized biases. Results: Marker concentrations in the six pelvic disease pools were generally within 0.25 SD of the actual average, and z values correlated well with sensitivities. CA 125 remains the best single marker for nonmucinous ovarian cancer, complemented by CA 15.3 or soluble mesothelin-related protein. There is no comparable breast cancer biomarker among the current analytes tested. Conclusion: The potential value of standard serum sets for initial assessment of candidate biomarkers is illustrated. Sets are now available through the Early Detection Research Network to evaluate biomarkers for women's cancers. Copyright © 2007 American Association for Cancer Research.

Authors
Skates, SJ; Horick, NK; Moy, JM; Minihan, AM; Seiden, MV; Marks, JR; Sluss, P; Cramer, DW
MLA Citation
Skates, SJ, Horick, NK, Moy, JM, Minihan, AM, Seiden, MV, Marks, JR, Sluss, P, and Cramer, DW. "Pooling of case specimens to create standard serum sets for screening cancer biomarkers." Cancer Epidemiology Biomarkers and Prevention 16.2 (2007): 334-341.
PMID
17301268
Source
scival
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
16
Issue
2
Publish Date
2007
Start Page
334
End Page
341
DOI
10.1158/1055-9965.EPI-06-0681

Genomic signatures to guide the use of chemotherapeutics.

Using in vitro drug sensitivity data coupled with Affymetrix microarray data, we developed gene expression signatures that predict sensitivity to individual chemotherapeutic drugs. Each signature was validated with response data from an independent set of cell line studies. We further show that many of these signatures can accurately predict clinical response in individuals treated with these drugs. Notably, signatures developed to predict response to individual agents, when combined, could also predict response to multidrug regimens. Finally, we integrated the chemotherapy response signatures with signatures of oncogenic pathway deregulation to identify new therapeutic strategies that make use of all available drugs. The development of gene expression profiles that can predict response to commonly used cytotoxic agents provides opportunities to better use these drugs, including using them in combination with existing targeted therapies.

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, RF, Chan, G, Sayer, R, Cragun, J, Cottrill, H, Kelley, MJ, Petersen, R, Harpole, D, Marks, J, Berchuck, A, Ginsburg, GS, Febbo, P, Lancaster, J, and Nevins, JR. "Genomic signatures to guide the use of chemotherapeutics." Nat Med 12.11 (November 2006): 1294-1300.
PMID
17057710
Source
pubmed
Published In
Nature Medicine
Volume
12
Issue
11
Publish Date
2006
Start Page
1294
End Page
1300
DOI
10.1038/nm1491

Identification of genes associated with ovarian cancer metastasis using microarray expression analysis.

Although the transition from early- to advanced-stage ovarian cancer is a critical determinant of survival, little is known about the molecular underpinnings of ovarian metastasis. We hypothesize that microarray analysis of global gene expression patterns in primary ovarian cancer and metastatic omental implants can identify genes that underlie the metastatic process in epithelial ovarian cancer. We utilized Affymetrix U95Av2 microarrays to characterize the molecular alterations that underlie omental metastasis from 47 epithelial ovarian cancer samples collected from multiple sites in 20 patients undergoing primary surgical cytoreduction for advanced-stage (IIIC/IV) serous ovarian cancer. Fifty-six genes demonstrated differential expression between ovarian and omental samples (P < 0.01), and twenty of these 56 differentially expressed genes have previously been implicated in metastasis, cell motility, or cytoskeletal function. Ten of the 56 genes are involved in p53 gene pathways. A Bayesian statistical tree analysis was used to identify a 27-gene expression pattern that could accurately predict the site of tumor (ovary versus omentum). This predictive model was evaluated using an external data set. Nine of the 27 predictive genes have previously been shown to be involved in oncogenesis and/or metastasis, and 10/27 genes have been implicated in p53 pathways. Microarray findings were validated by real-time quantitative PCR. We conclude that gene expression patterns that distinguish omental metastasis from primary epithelial ovarian cancer can be identified and that many of the genes have functions that are biologically consistent with a role in oncogenesis, metastasis, and p53 gene networks.

Authors
Lancaster, JM; Dressman, HK; Clarke, JP; Sayer, RA; Martino, MA; Cragun, JM; Henriott, AH; Gray, J; Sutphen, R; Elahi, A; Whitaker, RS; West, M; Marks, JR; Nevins, JR; Berchuck, A
MLA Citation
Lancaster, JM, Dressman, HK, Clarke, JP, Sayer, RA, Martino, MA, Cragun, JM, Henriott, AH, Gray, J, Sutphen, R, Elahi, A, Whitaker, RS, West, M, Marks, JR, Nevins, JR, and Berchuck, A. "Identification of genes associated with ovarian cancer metastasis using microarray expression analysis." Int J Gynecol Cancer 16.5 (September 2006): 1733-1745.
PMID
17009964
Source
pubmed
Published In
International Journal of Gynecological Cancer
Volume
16
Issue
5
Publish Date
2006
Start Page
1733
End Page
1745
DOI
10.1111/j.1525-1438.2006.00660.x

High expression of insulin-like growth factor binding protein-2 messenger RNA in epithelial ovarian cancers produces elevated preoperative serum levels.

The molecular etiology of epithelial ovarian cancer remains unclear. Using microarray expression analysis, we recently reported that expression of the insulin-like growth factor binding protein-2 (IGFBP-2) gene is elevated in advanced epithelial ovarian cancers. The aim of this study was to further delineate the role of IGFBP-2 in the pathoetiology of epithelial ovarian cancer and determine if elevated ovarian cancer IGFBP-2 gene expression is reflected in serum. Relative IGFBP-2 expression was measured using quantitative real-time polymerase chain reaction in 113 epithelial ovarian cancers and 6 normal ovarian surface epithelial samples. Preoperative serum IGFBP-2 levels were measured by radioimmunoassay in 84 women (42 ovarian cancers, 26 benign gynecological conditions, and 10 healthy female controls). Ovarian cancers demonstrated 38-fold higher mean IGFBP-2 expression than normal ovarian epithelium (P < 0.01). Serum IGFBP-2 levels were elevated in women with early- and advanced-stage ovarian cancer compared to controls and patients with benign gynecological conditions (P = 0.05 and P < 0.01, respectively). Epithelial ovarian cancers express high levels of IGFBP-2 relative to normal ovarian epithelium, and this is associated with elevated serum IGFBP-2 levels compared to both normal controls and patients with benign gynecological disease. Our findings provide further support that the insulin-like growth factor pathway plays a significant role in epithelial ovarian cancer pathogenesis. Further, IGFBP-2 may represent an additional serum biomarker with utility in detection and monitoring of epithelial ovarian cancer.

Authors
Lancaster, JM; Sayer, RA; Blanchette, C; Calingaert, B; Konidari, I; Gray, J; Schildkraut, J; Schomberg, DW; Marks, JR; Berchuck, A
MLA Citation
Lancaster, JM, Sayer, RA, Blanchette, C, Calingaert, B, Konidari, I, Gray, J, Schildkraut, J, Schomberg, DW, Marks, JR, and Berchuck, A. "High expression of insulin-like growth factor binding protein-2 messenger RNA in epithelial ovarian cancers produces elevated preoperative serum levels." Int J Gynecol Cancer 16.4 (July 2006): 1529-1535.
PMID
16884361
Source
pubmed
Published In
International Journal of Gynecological Cancer
Volume
16
Issue
4
Publish Date
2006
Start Page
1529
End Page
1535
DOI
10.1111/j.1525-1438.2006.00623.x

Maspin expression in epithelial ovarian cancer and associations with poor prognosis: a Gynecologic Oncology Group study.

OBJECTIVE: This study examined MASPIN expression in human ovarian cancer, and explored the association between MASPIN and prognosis in patients with advanced stage disease treated with first-line cisplatin, carboplatin and/or paclitaxel. METHODS: Frozen primary tumors were obtained from 68 women with previously untreated, advanced stage epithelial ovarian cancer who participated in a specimen banking protocol and a phase III treatment trial conducted by the Gynecologic Oncology Group. Immunoblot analysis was performed in lysates prepared from these tumor specimens to quantify the relative expression of MASPIN/beta-actin. RESULTS: MASPIN was expressed at detected levels in 49 (72%) cases with relative expression ranging from 0.02 to 7.7 (median = 0.2), and was not detected in 19 (28%) of the primary tumors tested. Non-detectable levels of this class II tumor suppressor gene product and inhibitor of angiogenesis were associated with suboptimally-debulked disease (P = 0.034) but not with patient age, FIGO stage, tumor grade, or histologic subtype. After adjusting for prognostic variables for disease progression or death, non-detectable MASPIN expression predicted an increased risk of disease progression (hazard ratio [HR] = 1.89; 95% confidence interval [CI]: 1.04-3.45; P = 0.038) and death (HR = 1.99; 95% CI: 1.07-3.69; P = 0.030). CONCLUSIONS: In advanced stage epithelial ovarian cancer, non-detectable MASPIN appears to be associated with suboptimally-debulked disease and be an independent predictor of an increased risk of progression and death. Further studies are needed to validate these exploratory findings, determine the molecular mechanism controlling MASPIN expression as well as down-regulation and loss in ovarian cancer, and determine if MASPIN can prevent progression of this disease.

Authors
Gynecologic Oncology Group, ; Secord, AA; Lee, PS; Darcy, KM; Havrilesky, LJ; Grace, LA; Marks, JR; Berchuck, A
MLA Citation
Gynecologic Oncology Group, , Secord, AA, Lee, PS, Darcy, KM, Havrilesky, LJ, Grace, LA, Marks, JR, and Berchuck, A. "Maspin expression in epithelial ovarian cancer and associations with poor prognosis: a Gynecologic Oncology Group study." Gynecol Oncol 101.3 (June 2006): 390-397.
PMID
16551475
Source
pubmed
Published In
Gynecologic Oncology
Volume
101
Issue
3
Publish Date
2006
Start Page
390
End Page
397
DOI
10.1016/j.ygyno.2006.02.014

Evaluation of expression based markers for the detection of breast cancer cells.

INTRODUCTION: Genes that are expressed in a highly tissue- or disease-specific manner provide possible targets for therapeutics, early detection of cancer, and monitoring of disease burden during and after treatment. Further, genes of this type that code for secreted or shed proteins may allow for serum detection of the product facilitating our ability to specifically detect the cancer in all circumstances. To this end, we are working towards identification and characterization of such genes that are specifically expressed in breast epithelium. In the current study, we have measured the expression of two markers that emerged from a screen of the Incyte LifeSeq Database and were subsequently shown to be highly restricted to breast epithelium termed BU101 (also called Lipophilin B) and BS106 (small mucin-like protein). These two novel markers were compared with two other candidate markers, Mammaglobin and Cytokeratin 19 (CK19). METHODS: Utilizing quantitative real-time PCR, we compared the expression of these four genes in a series of 95 primary breast cancers, 9 lymph nodes from breast cancer patients, 13 lymph nodes from non-cancer patients and 10 normal breast tissues. RESULTS: Cytokeratin was shown to be highly sensitive in detecting all breast cancers, while BU101, BS106 and Mammaglobin were more restricted. CONCLUSION: While no one of the these markers efficiently detects all breast cancers, a combination of two or more could achieve a very high sensitivity in assaying for circulating or occult breast cancer cells.

Authors
Brown, NM; Stenzel, TT; Friedman, PN; Henslee, J; Huper, G; Marks, JR
MLA Citation
Brown, NM, Stenzel, TT, Friedman, PN, Henslee, J, Huper, G, and Marks, JR. "Evaluation of expression based markers for the detection of breast cancer cells." Breast Cancer Res Treat 97.1 (May 2006): 41-47.
PMID
16319979
Source
pubmed
Published In
Breast Cancer Research and Treatment
Volume
97
Issue
1
Publish Date
2006
Start Page
41
End Page
47
DOI
10.1007/s10549-005-9085-8

Frequent IGF2/H19 domain epigenetic alterations and elevated IGF2 expression in epithelial ovarian cancer.

Overexpression of the imprinted insulin-like growth factor-II (IGF2) is a prominent characteristic of gynecologic malignancies. The purpose of this study was to determine whether IGF2 loss of imprinting (LOI), aberrant H19 expression, and/or epigenetic deregulation of the IGF2/H19 imprinted domain contributes to elevated IGF2 expression in serous epithelial ovarian tumors. IGF2 LOI was observed in 5 of 23 informative serous epithelial ovarian cancers, but this did not correlate with elevated expression of IGF2 H19 RNA expression levels were also found not to correlate with IGF2 transcript levels. However, we identified positive correlations between elevated IGF2 expression and hypermethylation of CCCTC transcription factor binding sites 1 and 6 at the H19 proximal imprint center (P = 0.05 and 0.02, respectively). Hypermethylation of CCCTC transcription factor sites 1 and 6 was observed more frequently in cancer DNA compared with lymphocyte DNA obtained from women without malignancy (P < 0.0001 for both sites 1 and 6). Ovarian cancers were also more likely to exhibit maternal allele-specific hypomethylation upstream of the imprinted IGF2 promoters when compared with normal lymphocyte DNA (P = 0.004). This is the same region shown previously to be hypomethylated in colon cancers with IGF2 LOI, but this was not associated with LOI in ovarian cancers. Elevated IGF2 expression is a frequent event in serous ovarian cancer and this occurs in the absence of IGF2 LOI. These data indicate that the epigenetic changes observed in these cancers at the imprint center may contribute to IGF2 overexpression in a novel mechanistic manner.

Authors
Murphy, SK; Huang, Z; Wen, Y; Spillman, MA; Whitaker, RS; Simel, LR; Nichols, TD; Marks, JR; Berchuck, A
MLA Citation
Murphy, SK, Huang, Z, Wen, Y, Spillman, MA, Whitaker, RS, Simel, LR, Nichols, TD, Marks, JR, and Berchuck, A. "Frequent IGF2/H19 domain epigenetic alterations and elevated IGF2 expression in epithelial ovarian cancer." Mol Cancer Res 4.4 (April 2006): 283-292.
PMID
16603642
Source
pubmed
Published In
Molecular cancer research : MCR
Volume
4
Issue
4
Publish Date
2006
Start Page
283
End Page
292
DOI
10.1158/1541-7786.MCR-05-0138

Enhanced sensitivity to cytochrome c-induced apoptosis mediated by PHAPI in breast cancer cells.

Apoptotic signaling defects both promote tumorigenesis and confound chemotherapy. Typically, chemotherapeutics stimulate cytochrome c release to the cytoplasm, thereby activating the apoptosome. Although cancer cells can be refractory to cytochrome c release, many malignant cells also exhibit defects in cytochrome c-induced apoptosome activation, further promoting chemotherapeutic resistance. We have found that breast cancer cells display an unusual sensitivity to cytochrome c-induced apoptosis when compared with their normal counterparts. This sensitivity, not observed in other cancers, resulted from enhanced recruitment of caspase-9 to the Apaf-1 caspase recruitment domain. Augmented caspase activation was mediated by PHAPI, which is overexpressed in breast cancers. Furthermore, cytochrome c microinjection into mammary epithelial cells preferentially killed malignant cells, suggesting that this phenomenon might be exploited for chemotherapeutic purposes.

Authors
Schafer, ZT; Parrish, AB; Wright, KM; Margolis, SS; Marks, JR; Deshmukh, M; Kornbluth, S
MLA Citation
Schafer, ZT, Parrish, AB, Wright, KM, Margolis, SS, Marks, JR, Deshmukh, M, and Kornbluth, S. "Enhanced sensitivity to cytochrome c-induced apoptosis mediated by PHAPI in breast cancer cells." Cancer Res 66.4 (February 15, 2006): 2210-2218.
PMID
16489023
Source
pubmed
Published In
Cancer Research
Volume
66
Issue
4
Publish Date
2006
Start Page
2210
End Page
2218
DOI
10.1158/0008-5472.CAN-05-3923

Gene expression profiles of multiple breast cancer phenotypes and response to neoadjuvant chemotherapy.

PURPOSE: Breast cancer is a heterogeneous disease, and markers for disease subtypes and therapy response remain poorly defined. For that reason, we employed a prospective neoadjuvant study in locally advanced breast cancer to identify molecular signatures of gene expression correlating with known prognostic clinical phenotypes, such as inflammatory breast cancer or the presence of hypoxia. In addition, we defined molecular signatures that correlate with response to neoadjuvant chemotherapy. EXPERIMENTAL DESIGN: Tissue was collected under ultrasound guidance from patients with stage IIB/III breast cancer before four cycles of neoadjuvant liposomal doxorubicin paclitaxel chemotherapy combined with local whole breast hyperthermia. Gene expression analysis was done using Affymetrix U133 Plus 2.0 GeneChip arrays. RESULTS: Gene expression patterns were identified that defined the phenotypes of inflammatory breast cancer as well as tumor hypoxia. In addition, molecular signatures were identified that predicted the persistence of malignancy in the axillary lymph nodes after neoadjuvant chemotherapy. This persistent lymph node signature significantly correlated with disease-free survival in two separate large populations of breast cancer patients. CONCLUSIONS: Gene expression signatures have the capacity to identify clinically significant features of breast cancer and can predict which individual patients are likely to be resistant to neoadjuvant therapy, thus providing the opportunity to guide treatment decisions.

Authors
Dressman, HK; Hans, C; Bild, A; Olson, JA; Rosen, E; Marcom, PK; Liotcheva, VB; Jones, EL; Vujaskovic, Z; Marks, J; Dewhirst, MW; West, M; Nevins, JR; Blackwell, K
MLA Citation
Dressman, HK, Hans, C, Bild, A, Olson, JA, Rosen, E, Marcom, PK, Liotcheva, VB, Jones, EL, Vujaskovic, Z, Marks, J, Dewhirst, MW, West, M, Nevins, JR, and Blackwell, K. "Gene expression profiles of multiple breast cancer phenotypes and response to neoadjuvant chemotherapy." Clin Cancer Res 12.3 Pt 1 (February 1, 2006): 819-826.
PMID
16467094
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
3 Pt 1
Publish Date
2006
Start Page
819
End Page
826
DOI
10.1158/1078-0432.CCR-05-1447

Oncogenic pathway signatures in human cancers as a guide to targeted therapies.

The development of an oncogenic state is a complex process involving the accumulation of multiple independent mutations that lead to deregulation of cell signalling pathways central to the control of cell growth and cell fate. The ability to define cancer subtypes, recurrence of disease and response to specific therapies using DNA microarray-based gene expression signatures has been demonstrated in multiple studies. Various studies have also demonstrated the potential for using gene expression profiles for the analysis of oncogenic pathways. Here we show that gene expression signatures can be identified that reflect the activation status of several oncogenic pathways. When evaluated in several large collections of human cancers, these gene expression signatures identify patterns of pathway deregulation in tumours and clinically relevant associations with disease outcomes. Combining signature-based predictions across several pathways identifies coordinated patterns of pathway deregulation that distinguish between specific cancers and tumour subtypes. Clustering tumours based on pathway signatures further defines prognosis in respective patient subsets, demonstrating that patterns of oncogenic pathway deregulation underlie the development of the oncogenic phenotype and reflect the biology and outcome of specific cancers. Predictions of pathway deregulation in cancer cell lines are also shown to predict the sensitivity to therapeutic agents that target components of the pathway. Linking pathway deregulation with sensitivity to therapeutics that target components of the pathway provides an opportunity to make use of these oncogenic pathway signatures to guide the use of targeted therapeutics.

Authors
Bild, AH; Yao, G; Chang, JT; Wang, Q; Potti, A; Chasse, D; Joshi, M-B; Harpole, D; Lancaster, JM; Berchuck, A; Olson, JA; Marks, JR; Dressman, HK; West, M; Nevins, JR
MLA Citation
Bild, AH, Yao, G, Chang, JT, Wang, Q, Potti, A, Chasse, D, Joshi, M-B, Harpole, D, Lancaster, JM, Berchuck, A, Olson, JA, Marks, JR, Dressman, HK, West, M, and Nevins, JR. "Oncogenic pathway signatures in human cancers as a guide to targeted therapies." Nature 439.7074 (January 19, 2006): 353-357.
PMID
16273092
Source
pubmed
Published In
Nature
Volume
439
Issue
7074
Publish Date
2006
Start Page
353
End Page
357
DOI
10.1038/nature04296

Analgesic drug use and risk of ovarian cancer.

BACKGROUND: Previous epidemiologic research suggests that analgesic use may reduce the risk of ovarian cancer, although results are not consistent. METHODS: In a population-based, case-control study, we analyzed data from 586 ovarian cancer cases and 627 matched controls in North Carolina for the relationship between analgesic use and ovarian cancer risk. Logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) while adjusting for potential confounders. RESULTS: Use of any nonsteroidal antiinflammatory drugs, including aspirin, within 5 years of diagnosis/interview was found to be associated with a reduction in the risk of ovarian cancer (adjusted OR = 0.72; 95% CI = 0.56-0.92). For use of acetaminophen, the OR was 0.78 (95% CI = 0.56-1.08). CONCLUSIONS: These data support an inverse relationship between the use of both nonsteroidal antiinflammatory drugs and acetaminophen and the risk of ovarian cancer.

Authors
Schildkraut, JM; Moorman, PG; Halabi, S; Calingaert, B; Marks, JR; Berchuck, A
MLA Citation
Schildkraut, JM, Moorman, PG, Halabi, S, Calingaert, B, Marks, JR, and Berchuck, A. "Analgesic drug use and risk of ovarian cancer." Epidemiology 17.1 (January 2006): 104-107.
PMID
16357602
Source
pubmed
Published In
Epidemiology
Volume
17
Issue
1
Publish Date
2006
Start Page
104
End Page
107

Combined cDNA array comparative genomic hybridization and serial analysis of gene expression analysis of breast tumor progression

To identify genetic changes involved in the progression of breast carcinoma, we did cDNA array comparative genomic hybridization (CGH) on a panel of breast tumors, including 10 ductal carcinoma in situ (DCIS), 18 invasive breast carcinomas, and two lymph node metastases. We identified 49 minimal commonly amplified regions (MCRs) that included known (1q, 8q24, 11q13, 17q21-q23, and 20q13) and several uncharacterized (12p13 and 16p13) regional copy number gains. With the exception of the 17q21 (ERBB2) amplicon, the overall frequency of copy number alterations was higher in invasive tumors than that in DCIS, with several of them present only in invasive cancer. Amplification of candidate loci was confirmed by quantitative PCR in breast carcinomas and cell lines. To identify putative targets of amplicons, we developed a method combining array CGH and serial analysis of gene expression (SAGE) data to correlate copy number and expression levels for each gene within MCRs. Using this approach, we were able to distinguish a few candidate targets from a set of coamplified genes. Analysis of the 12p13-p12 amplicon identified four putative targets: TEL/ETV6, H2AFJ, EPS8, and KRAS2. The amplification of all four candidates was confirmed by quantitative PCR and fluorescence in situ hybridization, but only H2AFJ and EPS8 were overexpressed in breast tumors with 12p13 amplification compared with a panel of normal mammary epithelial cells. These results show the power of combined array CGH and SAGE analysis for the identification of candidate amplicon targets and identify H2AFJ and EPS8 as novel putative oncogenes in breast cancer. ©2006 American Association for Cancer Research.

Authors
Yao, J; Weremowicz, S; Feng, B; Gentleman, RC; Marks, JR; Gelman, R; Brennan, C; Polyak, K
MLA Citation
Yao, J, Weremowicz, S, Feng, B, Gentleman, RC, Marks, JR, Gelman, R, Brennan, C, and Polyak, K. "Combined cDNA array comparative genomic hybridization and serial analysis of gene expression analysis of breast tumor progression." Cancer Research 66.8 (2006): 4065-4078.
PMID
16618726
Source
scival
Published In
Cancer Research
Volume
66
Issue
8
Publish Date
2006
Start Page
4065
End Page
4078
DOI
10.1158/0008-5472.CAN-05-4083

High throughput detection of M6P/IGF2R intronic hypermethylation and LOH in ovarian cancer.

Cell surface mannose 6-phosphate/insulin-like growth factor II receptors (M6P/IGF2R) bind and target exogenous insulin-like growth factor II (IGF2) to the prelysosomes where it is degraded. Loss of heterozygosity (LOH) for M6P/IGF2R is found in cancers, with mutational inactivation of the remaining allele. We exploited the normal allele-specific differential methylation of the M6P/IGF2R intron 2 CpG island to rapidly evaluate potential LOH in ovarian cancers, since every normal individual is informative. To this end, we developed a method for bisulfite modification of genomic DNA in 96-well format that allows for rapid methylation profiling. We identified ovarian cancers with M6P/IGF2R LOH, but unexpectedly also found frequent abnormal acquisition of methylation on the paternally inherited allele at intron 2. These results demonstrate the utility of our high-throughput method of bisulfite modification for analysis of large sample numbers. They further show that the methylation status of the intron 2 CpG island may be a useful indicator of LOH and biomarker of disease.

Authors
Huang, Z; Wen, Y; Shandilya, R; Marks, JR; Berchuck, A; Murphy, SK
MLA Citation
Huang, Z, Wen, Y, Shandilya, R, Marks, JR, Berchuck, A, and Murphy, SK. "High throughput detection of M6P/IGF2R intronic hypermethylation and LOH in ovarian cancer. (Published online)" Nucleic Acids Res 34.2 (2006): 555-563.
PMID
16432260
Source
pubmed
Published In
Nucleic Acids Research
Volume
34
Issue
2
Publish Date
2006
Start Page
555
End Page
563
DOI
10.1093/nar/gkj468

Associations between drug metabolism genotype, chemotherapy pharmacokinetics, and overall survival in patients with breast cancer.

PURPOSE: To evaluate associations between patient survival, pharmacokinetics, and drug metabolism-related genetic polymorphisms in patients receiving a combination chemotherapy regimen for breast cancer. PATIENTS AND METHODS: A genotype association study was conducted on 85 chemotherapy-naïve patients with metastatic or inflammatory breast cancer that were evaluated for an extended period after receiving standard-dose chemotherapy followed by high-dose cyclophosphamide, cisplatin, and carmustine. Blood pharmacokinetics were evaluated, and DNA was genotyped for 29 polymorphisms in 17 drug metabolism genes. RESULTS: Patients with cyclophosphamide plasma exposures above the median (implying slower metabolic activation) had a shorter survival than those below the median (1.8 v 3.8 years, respectively; P = .042). Patients having a variant genotype of cytochrome P450 3A4 displayed higher blood concentrations of parent (inactive) cyclophosphamide with the second and third doses (P = .024 and .028, respectively) in addition to slower cyclophosphamide activation over the three doses (P = .031). Median survival for these patients was 1.3 years compared with 2.7 years for those without the variant (P = .043). Similar results were observed for patients carrying a genetic variant of P450 3A5. Median survival for patients with deletions of glutathione-S-transferase M1 gene was 3.5 v 1.5 years for patients with one or both copies (P = .041). Patients with a polymorphism in a gene regulating metallothionein had lower platinum concentrations and shorter survival (P = .033). CONCLUSION: These data suggest that pretreatment evaluation of drug metabolism genes may explain some interindividual differences in both anticancer drug pharmacokinetics and response. The correlations found here may have implications for other commonly used anticancer drugs.

Authors
Petros, WP; Hopkins, PJ; Spruill, S; Broadwater, G; Vredenburgh, JJ; Colvin, OM; Peters, WP; Jones, RB; Hall, J; Marks, JR
MLA Citation
Petros, WP, Hopkins, PJ, Spruill, S, Broadwater, G, Vredenburgh, JJ, Colvin, OM, Peters, WP, Jones, RB, Hall, J, and Marks, JR. "Associations between drug metabolism genotype, chemotherapy pharmacokinetics, and overall survival in patients with breast cancer." J Clin Oncol 23.25 (September 1, 2005): 6117-6125.
PMID
16087946
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
23
Issue
25
Publish Date
2005
Start Page
6117
End Page
6125
DOI
10.1200/JCO.2005.06.075

Patterns of gene expression that characterize long-term survival in advanced stage serous ovarian cancers.

PURPOSE: A better understanding of the underlying biology of invasive serous ovarian cancer is critical for the development of early detection strategies and new therapeutics. The objective of this study was to define gene expression patterns associated with favorable survival. EXPERIMENTAL DESIGN: RNA from 65 serous ovarian cancers was analyzed using Affymetrix U133A microarrays. This included 54 stage III/IV cases (30 short-term survivors who lived <3 years and 24 long-term survivors who lived >7 years) and 11 stage I/II cases. Genes were screened on the basis of their level of and variability in expression, leaving 7,821 for use in developing a predictive model for survival. A composite predictive model was developed that combines Bayesian classification tree and multivariate discriminant models. Leave-one-out cross-validation was used to select and evaluate models. RESULTS: Patterns of genes were identified that distinguish short-term and long-term ovarian cancer survivors. The expression model developed for advanced stage disease classified all 11 early-stage ovarian cancers as long-term survivors. The MAL gene, which has been shown to confer resistance to cancer therapy, was most highly overexpressed in short-term survivors (3-fold compared with long-term survivors, and 29-fold compared with early-stage cases). These results suggest that gene expression patterns underlie differences in outcome, and an examination of the genes that provide this discrimination reveals that many are implicated in processes that define the malignant phenotype. CONCLUSIONS: Differences in survival of advanced ovarian cancers are reflected by distinct patterns of gene expression. This biological distinction is further emphasized by the finding that early-stage cancers share expression patterns with the advanced stage long-term survivors, suggesting a shared favorable biology.

Authors
Berchuck, A; Iversen, ES; Lancaster, JM; Pittman, J; Luo, J; Lee, P; Murphy, S; Dressman, HK; Febbo, PG; West, M; Nevins, JR; Marks, JR
MLA Citation
Berchuck, A, Iversen, ES, Lancaster, JM, Pittman, J, Luo, J, Lee, P, Murphy, S, Dressman, HK, Febbo, PG, West, M, Nevins, JR, and Marks, JR. "Patterns of gene expression that characterize long-term survival in advanced stage serous ovarian cancers." Clin Cancer Res 11.10 (May 15, 2005): 3686-3696.
PMID
15897565
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
10
Publish Date
2005
Start Page
3686
End Page
3696
DOI
10.1158/1078-0432.CCR-04-2398

Transforming growth factor beta receptor I polyalanine repeat polymorphism does not increase ovarian cancer risk.

OBJECTIVES: It has been suggested that the 6A allele of the type I TGFbeta receptor (TGFbetaR1) polyalanine repeat tract polymorphism may increase susceptibility to various types of cancer including ovarian cancer. METHODS: The TGFbetaR1 polyalanine polymorphism was genotyped in 588 ovarian cancer cases and 614 controls from a population-based case-control study in North Carolina. RESULTS: Significant racial differences in the frequency of the 6A allele were observed between Caucasian (10.7%) and African-American (2.4%) controls (P < 0.001). One or two copies of the 6A allele of the TGFbetaR1 polyalanine polymorphism was carried by 18% of all controls and 19% of cases, and there was no association with ovarian cancer risk (OR = 1.07, 95% CI 0.80-1.44). The odds ratio for 6A homozygotes was 1.81 (95% CI 0.655.06), but these comprised only 0.98% of controls and 1.70% of cases. CONCLUSIONS: The 6A allele of the TGFbetaR1 polyalanine polymorphism does not appear to increase ovarian cancer risk. Larger studies would be needed to exclude the possibility that the small fraction of individuals who are 6A homozygotes have an increased risk of ovarian or other cancers.

Authors
Spillman, MA; Schildkraut, JM; Halabi, S; Moorman, P; Calingaert, B; Bentley, RC; Marks, JR; Murphy, S; Berchuck, A
MLA Citation
Spillman, MA, Schildkraut, JM, Halabi, S, Moorman, P, Calingaert, B, Bentley, RC, Marks, JR, Murphy, S, and Berchuck, A. "Transforming growth factor beta receptor I polyalanine repeat polymorphism does not increase ovarian cancer risk." Gynecol Oncol 97.2 (May 2005): 543-549.
PMID
15863158
Source
pubmed
Published In
Gynecologic Oncology
Volume
97
Issue
2
Publish Date
2005
Start Page
543
End Page
549
DOI
10.1016/j.ygyno.2005.01.025

Analysis of methylation-sensitive transcriptome identifies GADD45a as a frequently methylated gene in breast cancer.

Treatment of the breast cancer cell line, MDAMB468 with the DNA methylation inhibitor, 5-azacytidine (5-AzaC) results in growth arrest, whereas the growth of the normal breast epithelial line DU99 (telomerase immortalized) is relatively unaffected. Comparing gene expression profiles of these two lines after 5-AzaC treatment, we identified 36 genes that had relatively low basal levels in MDAMB468 cells compared to the DU99 line and were induced in the cancer cell line but not in the normal breast epithelial line. Of these genes, 33 have associated CpG islands greater than 300 bp in length but only three have been previously described as targets for aberrant methylation in human cancer. Northern blotting for five of these genes (alpha-Catenin, DTR, FYN, GADD45a, and Zyxin) verified the array results. Further analysis of one of these genes, GADD45a, showed that 5-AzaC induced expression in five additional breast cancer cell lines with little or no induction in three additional lines derived from normal breast epithelial cells. The CpG island associated with GADD45a was analysed by bisulfite sequencing, sampling over 100 CpG dinucleotides. We found that four CpG's, located approximately 700 bp upstream of the transcriptional start site are methylated in the majority of breast cancer cell lines and primary tumors but not in DNA from normal breast epithelia or matched lymphocytes from cancer patients. Therefore, this simple method of dynamic transcriptional profiling yielded a series of novel methylation-sensitive genes in breast cancer including the BRCA1 and p53 responsive gene, GADD45a.

Authors
Wang, W; Huper, G; Guo, Y; Murphy, SK; Olson, JA; Marks, JR
MLA Citation
Wang, W, Huper, G, Guo, Y, Murphy, SK, Olson, JA, and Marks, JR. "Analysis of methylation-sensitive transcriptome identifies GADD45a as a frequently methylated gene in breast cancer." Oncogene 24.16 (April 14, 2005): 2705-2714.
PMID
15735726
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
24
Issue
16
Publish Date
2005
Start Page
2705
End Page
2714
DOI
10.1038/sj.onc.1208464

High insulin-like growth factor-2 (IGF-2) gene expression is an independent predictor of poor survival for patients with advanced stage serous epithelial ovarian cancer.

OBJECTIVE: Epithelial ovarian cancer is the deadliest gynecologic malignancy, yet its molecular etiology remains poorly understood. Evidence is accumulating to support a role for the insulin-like growth factor family in human carcinogenesis, and recently using microarray expression analysis, we demonstrated over-expression of the insulin-like growth factor-2 (IGF-2) gene in advanced stage epithelial ovarian cancers. The purpose of the current study is to further elucidate the role of the IGF-2 gene in ovarian cancer development and progression. METHODS: Relative expression of IGF-2 was measured in 109 epithelial ovarian cancers and eight normal ovarian surface epithelial (NOSE) samples, using quantitative real-time polymerase chain reaction. Associations with clinicopathological parameters were examined. RESULTS: Expression of the IGF-2 gene was more than 300-fold higher in ovarian cancers compared with normal ovarian surface epithelium samples (P <0.001). High IGF-2 expression was associated with advanced stage disease at diagnosis (P <0.001), high-grade cancers (P <0.05) and sub-optimal surgical cytoreduction (P = 0.08). In multivariate analysis, relative IGF-2 expression was an independent predictor of poor survival. CONCLUSIONS: Expression of the IGF-2 gene is significantly higher in ovarian cancers relative to normal ovarian surface epithelium. Further, high IGF-2 gene expression is associated with high grade, advanced stage disease, and is an independent predictor of poor survival in patients with epithelial ovarian cancer. As such, IGF-2 is a molecular marker and potential therapeutic target for the most aggressive epithelial ovarian cancers.

Authors
Sayer, RA; Lancaster, JM; Pittman, J; Gray, J; Whitaker, R; Marks, JR; Berchuck, A
MLA Citation
Sayer, RA, Lancaster, JM, Pittman, J, Gray, J, Whitaker, R, Marks, JR, and Berchuck, A. "High insulin-like growth factor-2 (IGF-2) gene expression is an independent predictor of poor survival for patients with advanced stage serous epithelial ovarian cancer." Gynecol Oncol 96.2 (February 2005): 355-361.
PMID
15661221
Source
pubmed
Published In
Gynecologic Oncology
Volume
96
Issue
2
Publish Date
2005
Start Page
355
End Page
361
DOI
10.1016/j.ygyno.2004.10.012

IGF1 (CA)19 repeat and IGFBP3 -202 A/C genotypes and the risk of prostate cancer in Black and White men.

We investigated the relationship between the insulin-like growth factor-1 (IGF1) cytosine-adenine repeat (CA)(19) polymorphism located upstream of the gene's transcription start site, the insulin-like growth factor binding protein-3 (IGFBP3) -202 A/C promoter region polymorphism, and prostate cancer risk in Black and White men. Study subjects were U.S. veterans ages 41 to 75 years identified at the Durham Veterans Administration Medical Center over a 2.5-year period. Controls (n = 93) were frequency matched to cases (n = 100) based on race (Black or White) and age. Multivariable unconditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for the associations between the polymorphisms and prostate cancer risk. For Blacks and Whites combined, an inverse association between prostate cancer and being homozygous for the most common IGF1 repeat allele, (CA)(19), (adjusted OR, 0.3; 95% CI, 0.1-0.7) was observed. Similar associations were noted for both Blacks (OR, 0.2; 95% CI, 0.0-0.8) and Whites (OR, 0.4; 95% CI, 0.1-1.6) separately. No statistically significant associations between the IGFBP3 C allele and prostate cancer were noted for Blacks (adjusted OR, 2.3; 95% CI, 0.8-6.2) or Whites (OR, 1.0; 95% CI, 0.3-3.1). The prevalence of the homozygous IGF1 (CA)(19) genotype was much lower in Black controls (21%) than White controls (46%), which may, in part, explain the increased prostate cancer incidence in Black versus White men. Further research is needed to confirm these findings.

Authors
Schildkraut, JM; Demark-Wahnefried, W; Wenham, RM; Grubber, J; Jeffreys, AS; Grambow, SC; Marks, JR; Moorman, PG; Hoyo, C; Ali, S; Walther, PJ
MLA Citation
Schildkraut, JM, Demark-Wahnefried, W, Wenham, RM, Grubber, J, Jeffreys, AS, Grambow, SC, Marks, JR, Moorman, PG, Hoyo, C, Ali, S, and Walther, PJ. "IGF1 (CA)19 repeat and IGFBP3 -202 A/C genotypes and the risk of prostate cancer in Black and White men." Cancer Epidemiol Biomarkers Prev 14.2 (February 2005): 403-408.
PMID
15734965
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
14
Issue
2
Publish Date
2005
Start Page
403
End Page
408
DOI
10.1158/1055-9965.EPI-04-0426

Application of clinico-genomic models that predict breast cancer characteristics in a prospective study

Authors
Tebbit, CL; Pittman, J; Ellis, MJ; Bentley, R; Dressman, H; Mann, G; Leight, GS; Nevins, J; Marks, JR; Olson, JA
MLA Citation
Tebbit, CL, Pittman, J, Ellis, MJ, Bentley, R, Dressman, H, Mann, G, Leight, GS, Nevins, J, Marks, JR, and Olson, JA. "Application of clinico-genomic models that predict breast cancer characteristics in a prospective study." February 2005.
Source
wos-lite
Published In
Annals of Surgical Oncology
Volume
12
Issue
2
Publish Date
2005
Start Page
S68
End Page
S68

Progesterone receptor promoter +331A polymorphism is associated with a reduced risk of endometrioid and clear cell ovarian cancers.

OBJECTIVE: The progestagenic milieu of pregnancy and oral contraceptive use is protective against epithelial ovarian cancer. A functional single nucleotide polymorphism in the promoter of the progesterone receptor (+331A) alters the relative abundance of the A and B isoforms and has been associated with an increased risk of endometrial and breast cancer. In this study, we sought to determine whether this polymorphism affects ovarian cancer risk. METHODS: The +331G/A polymorphism was genotyped in a population-based, case-control study from North Carolina that included 942 Caucasian subjects (438 cases, 504 controls) and in a confirmatory group from Australia (535 cases, 298 controls). Logistic regression analysis was used to calculate age-adjusted odds ratios (OR). RESULTS: There was a suggestion of a protective effect of the +331A allele (AA or GA) against ovarian cancer in the North Carolina study [OR, 0.72; 95% confidence interval (95% CI), 0.47-1.10]. Examination of genotype frequencies by histologic type revealed that this was due to a decreased risk of endometrioid and clear cell cancers (OR, 0.30; 95% CI, 0.09-0.97). Similarly, in the Australian study, there was a nonsignificant decrease in the risk of ovarian cancer among those with the +331A allele (OR, 0.83; 95% CI, 0.51-1.35) that was strongest in the endometrioid/clear cell group (OR, 0.60; 95% CI, 0.24-1.44). In the combined U.S.-Australian data that included 174 endometrioid/clear cell cases (166 invasive, 8 borderline), the +331A allele was significantly associated with protection against this subset of ovarian cancers (OR, 0.46; 95% CI, 0.23-0.92). Preliminary evidence of a protective effect of the +331A allele against endometriosis was also noted in control subjects (OR, 0.19; 95% CI, 0.03-1.38). CONCLUSIONS: These findings suggest that the +331G/A progesterone receptor promoter polymorphism may modify the molecular epidemiologic pathway that encompasses both the development of endometriosis and its subsequent transformation into endometrioid/clear cell ovarian cancer.

Authors
Berchuck, A; Schildkraut, JM; Wenham, RM; Calingaert, B; Ali, S; Henriott, A; Halabi, S; Rodriguez, GC; Gertig, D; Purdie, DM; Kelemen, L; Spurdle, AB; Marks, J; Chenevix-Trench, G
MLA Citation
Berchuck, A, Schildkraut, JM, Wenham, RM, Calingaert, B, Ali, S, Henriott, A, Halabi, S, Rodriguez, GC, Gertig, D, Purdie, DM, Kelemen, L, Spurdle, AB, Marks, J, and Chenevix-Trench, G. "Progesterone receptor promoter +331A polymorphism is associated with a reduced risk of endometrioid and clear cell ovarian cancers." Cancer Epidemiol Biomarkers Prev 13.12 (December 2004): 2141-2147.
PMID
15598772
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
13
Issue
12
Publish Date
2004
Start Page
2141
End Page
2147

Gene expression signature characterizing cyclin E protein overexpression in primary breast tumors

Authors
Tebbit, CL; Marks, JR; Dressman, H; Blanchette, C; Iverson, E; Pittman, J; Olson, JA
MLA Citation
Tebbit, CL, Marks, JR, Dressman, H, Blanchette, C, Iverson, E, Pittman, J, and Olson, JA. "Gene expression signature characterizing cyclin E protein overexpression in primary breast tumors." September 2004.
Source
wos-lite
Published In
Journal of The American College of Surgeons
Volume
199
Issue
3
Publish Date
2004
Start Page
S78
End Page
S79

TAFII70 isoform-specific growth suppression correlates with its ability to complex with the GADD45a protein.

TAFII70, a member of the basal transcription complex implicated in p53-mediated transcription, is synthesized as several alternately spliced variants. The predominant forms found in normal and neoplastic breast epithelial cells are shown to be 72 kDa (TAFII70) and 78 kDa (TAFII80). Most cancers express higher levels of the TAFII80 isoform, whereas normal breast epithelia express higher levels of the TAFII70 isoform. Expression of TAFII70, but not TAFII80, causes dramatic growth suppression of normal and transformed breast epithelial cell lines in a p53-independent manner. Growth suppression correlates with mitotic inhibition resulting from an increased number of cells in G2. Both isoforms induce expression of the G2 arrest associated gene, GADD45a, but a novel protein-protein interaction was observed between TAFII70 (not TAFII80) and GADD45a, suggesting that this interaction is important for the observed growth arrest phenotype induced by the TAFII70 isoform. GADD45a null cells are not subject to TAFII70 inhibition, further supporting the relevance of this interaction.

Authors
Wang, W; Nahta, R; Huper, G; Marks, JR
MLA Citation
Wang, W, Nahta, R, Huper, G, and Marks, JR. "TAFII70 isoform-specific growth suppression correlates with its ability to complex with the GADD45a protein." Mol Cancer Res 2.8 (August 2004): 442-452.
PMID
15328371
Source
pubmed
Published In
Molecular cancer research : MCR
Volume
2
Issue
8
Publish Date
2004
Start Page
442
End Page
452

Treatment of intracerebral neoplasia and neoplastic meningitis with regional delivery of oncolytic recombinant poliovirus.

PURPOSE: Spread to the central nervous system (CNS) and the leptomeninges is a frequent complication of systemic cancers that is associated with serious morbidity and high mortality. We have evaluated a novel therapeutic approach against CNS complications of breast cancer based on the human neuropathogen poliovirus (PV). EXPERIMENTAL DESIGN: Susceptibility to PV infection and ensuing rapid cell lysis is mediated by the cellular receptor of PV, CD155. We evaluated CD155 expression in several human breast tumor tissue specimens and cultured breast cancer cell lines. In addition, we tested an oncolytic PV recombinant for efficacy in xenotransplantation models of neoplastic meningitis and cerebral metastasis secondary to breast cancer. RESULTS: We observed that breast cancer tissues and cell lines derived thereof express CD155 at levels mediating exquisite sensitivity toward PV-induced oncolysis in the latter. An association with the immunoglobulin superfamily molecule CD155 renders breast cancer a likely target for oncolytic PV recombinants. This assumption was confirmed in xenotransplantation models for neoplastic meningitis or solitary cerebral metastasis, where local virus treatment dramatically improved survival. CONCLUSIONS: Our findings suggest oncolytic PV recombinants as a viable treatment option for CNS complications of breast cancer.

Authors
Ochiai, H; Moore, SA; Archer, GE; Okamura, T; Chewning, TA; Marks, JR; Sampson, JH; Gromeier, M
MLA Citation
Ochiai, H, Moore, SA, Archer, GE, Okamura, T, Chewning, TA, Marks, JR, Sampson, JH, and Gromeier, M. "Treatment of intracerebral neoplasia and neoplastic meningitis with regional delivery of oncolytic recombinant poliovirus." Clin Cancer Res 10.14 (July 15, 2004): 4831-4838.
PMID
15269159
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
10
Issue
14
Publish Date
2004
Start Page
4831
End Page
4838
DOI
10.1158/1078-0432.CCR-03-0694

Acquired expression of periostin by human breast cancers promotes tumor angiogenesis through up-regulation of vascular endothelial growth factor receptor 2 expression.

The late stages of human breast cancer development are poorly understood complex processes associated with the expression of genes by cancers that promote specific tumorigenic activities, such as angiogenesis. Here, we describe the identification of periostin as a mesenchyme-specific gene whose acquired expression by human breast cancers leads to a significant enhancement in tumor progression and angiogenesis. Undetectable in normal human breast tissues, periostin was found to be overexpressed by the vast majority of human primary breast cancers examined. Tumor cell lines engineered to overexpress periostin showed a phenotype of accelerated growth and angiogenesis as xenografts in immunocompromised animals. The underlying mechanism of periostin-mediated induction of angiogenesis was found to derive in part from the up-regulation of the vascular endothelial growth factor receptor Flk-1/KDR by endothelial cells through an integrin alpha(v)beta(3)-focal adhesion kinase-mediated signaling pathway. These findings demonstrate the presence of a novel mechanism by which tumor angiogenesis is acquired with the expression of a mesenchyme-specific gene as a crucial step in late stages of tumorigenesis.

Authors
Shao, R; Bao, S; Bai, X; Blanchette, C; Anderson, RM; Dang, T; Gishizky, ML; Marks, JR; Wang, X-F
MLA Citation
Shao, R, Bao, S, Bai, X, Blanchette, C, Anderson, RM, Dang, T, Gishizky, ML, Marks, JR, and Wang, X-F. "Acquired expression of periostin by human breast cancers promotes tumor angiogenesis through up-regulation of vascular endothelial growth factor receptor 2 expression." Mol Cell Biol 24.9 (May 2004): 3992-4003.
PMID
15082792
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
24
Issue
9
Publish Date
2004
Start Page
3992
End Page
4003

Estrogen receptor alpha (ESR1) mutant A908G is not a common feature in benign and malignant proliferations of the breast.

Alterations in estrogen responsive pathways are thought to contribute to benign and malignant breast disease. It has been reported previously that more than a third of typical epithelial hyperplasia lesions harbor the missense mutation A908G in the estrogen receptor alpha (ESR1) gene. This substitution of an arginine for a lysine at codon 303 was reported to confer mitogenic hypersensitivity to estrogen. To explore this finding further, we analyzed ESR1 for this mutation in a series of breast tissues ranging from typical hyperplasia to invasive cancer. In contrast to previous studies, no evidence for this mutation was found in 36 invasive cancers, 11 in situ carcinomas, 14 epithelial hyperplasias with atypia, 11 epithelial hyperplasias without atypia, and 11 breast cancer cell lines. These results indicate that ESR1 mutant A908G does not occur with significant frequency in either benign or malignant proliferations of breast epithelia.

Authors
Tebbit, CL; Bentley, RC; Olson, JA; Marks, JR
MLA Citation
Tebbit, CL, Bentley, RC, Olson, JA, and Marks, JR. "Estrogen receptor alpha (ESR1) mutant A908G is not a common feature in benign and malignant proliferations of the breast." Genes Chromosomes Cancer 40.1 (May 2004): 51-54.
PMID
15034868
Source
pubmed
Published In
Genes, Chromosomes and Cancer
Volume
40
Issue
1
Publish Date
2004
Start Page
51
End Page
54
DOI
10.1002/gcc.20017

Cell cycle progression in G1 and S phases is CCR4 dependent following ionizing radiation or replication stress in Saccharomyces cerevisiae.

To identify new nonessential genes that affect genome integrity, we completed a screening for diploid mutant Saccharomyces cerevisiae strains that are sensitive to ionizing radiation (IR) and found 62 new genes that confer resistance. Along with those previously reported (Bennett et al., Nat. Genet. 29:426-434, 2001), these genes bring to 169 the total number of new IR resistance genes identified. Through the use of existing genetic and proteomic databases, many of these genes were found to interact in a damage response network with the transcription factor Ccr4, a core component of the CCR4-NOT and RNA polymerase-associated factor 1 (PAF1)-CDC73 transcription complexes. Deletions of individual members of these two complexes render cells sensitive to the lethal effects of IR as diploids, but not as haploids, indicating that the diploid G1 cell population is radiosensitive. Consistent with a role in G1, diploid ccr4Delta cells irradiated in G1 show enhanced lethality compared to cells exposed as a synchronous G2 population. In addition, a prolonged RAD9-dependent G1 arrest occurred following IR of ccr4Delta cells and CCR4 is a member of the RAD9 epistasis group, thus confirming a role for CCR4 in checkpoint control. Moreover, ccr4Delta cells that transit S phase in the presence of the replication inhibitor hydroxyurea (HU) undergo prolonged cell cycle arrest at G2 followed by cellular lysis. This S-phase replication defect is separate from that seen for rad52 mutants, since rad52Delta ccr4Delta cells show increased sensitivity to HU compared to rad52Delta or ccr4Delta mutants alone. These results indicate that cell cycle transition through G1 and S phases is CCR4 dependent following radiation or replication stress.

Authors
Westmoreland, TJ; Marks, JR; Olson, JA; Thompson, EM; Resnick, MA; Bennett, CB
MLA Citation
Westmoreland, TJ, Marks, JR, Olson, JA, Thompson, EM, Resnick, MA, and Bennett, CB. "Cell cycle progression in G1 and S phases is CCR4 dependent following ionizing radiation or replication stress in Saccharomyces cerevisiae." Eukaryot Cell 3.2 (April 2004): 430-446.
PMID
15075273
Source
pubmed
Published In
Eukaryotic cell
Volume
3
Issue
2
Publish Date
2004
Start Page
430
End Page
446

Prediction of optimal versus suboptimal cytoreduction of advanced-stage serous ovarian cancer with the use of microarrays.

OBJECTIVE: The purpose of this study was to define gene expression patterns that are associated with the optimal versus suboptimal debulking of advanced-stage serous ovarian cancers. STUDY DESIGN: RNA from 44 advanced serous ovarian cancers (19 optimal, 25 suboptimal) was evaluated with microarrays that contain >22,000 genes. Genes were screened on the basis of their association with debulking status to obtain the top 120 differentially expressed genes. These genes were then used to develop a predictive model for debulking status, which was subjected to out-of-sample cross validation. RESULTS: We found that patterns of expression of 32 genes can distinguish between optimal and suboptimal debulking with 72.7% predictive accuracy. An analysis of the data that were based on clusters of co-ordinately expressed genes resulted in only a marginal improvement in predictive accuracy (75%). CONCLUSION: These data support the hypothesis that favorable survival that is associated with optimal debulking of advanced ovarian cancers is due to, at least in part, the underlying biologic characteristics of these cancers.

Authors
Berchuck, A; Iversen, ES; Lancaster, JM; Dressman, HK; West, M; Nevins, JR; Marks, JR
MLA Citation
Berchuck, A, Iversen, ES, Lancaster, JM, Dressman, HK, West, M, Nevins, JR, and Marks, JR. "Prediction of optimal versus suboptimal cytoreduction of advanced-stage serous ovarian cancer with the use of microarrays." Am J Obstet Gynecol 190.4 (April 2004): 910-925.
PMID
15118612
Source
pubmed
Published In
American Journal of Obstetrics & Gynecology
Volume
190
Issue
4
Publish Date
2004
Start Page
910
End Page
925
DOI
10.1016/j.ajog.2004.02.005

Prediction of long-term versus short-term survival in advanced stage serous ovarian cancer using expression microarrays.

Authors
Berchuck, A; Iversen, E; Lancaster, JM; Henriott, A; Dressman, H; West, M; Nevins, JR; Marks, JR
MLA Citation
Berchuck, A, Iversen, E, Lancaster, JM, Henriott, A, Dressman, H, West, M, Nevins, JR, and Marks, JR. "Prediction of long-term versus short-term survival in advanced stage serous ovarian cancer using expression microarrays." February 2004.
Source
wos-lite
Published In
Journal of the Society for Gynecologic Investigation (Elsevier)
Volume
11
Issue
2
Publish Date
2004
Start Page
182A
End Page
182A

Gene expression patterns that characterize advanced stage serous ovarian cancers.

OBJECTIVE: To identify gene expression patterns that characterize advanced stage serous ovarian cancers by using microarray expression analysis. METHODS: Using genome-wide expression analysis, we compared a series of 31 advanced stage (III or IV) serous ovarian cancers from patients who survived either less than 2 years or more than 7 years with three normal ovarian epithelial samples. Array findings were validated by analysis of expression of the insulin-like growth factor binding protein 2 (IGFBP2) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) genes using quantitative real-time polymerase chain reaction (QRT-PCR). RESULTS: Hierarchical clustering identified patterns of gene expression that distinguished cancer from normal ovarian epithelium. We also identified gene expression patterns that distinguish cancers on the basis of patient survival. These genes include many that are associated with immune function. Expression of IGFBP2 and TRAIL genes measured by array and QRT-PCR analysis demonstrated correlation coefficients of 0.63 and 0.78, respectively. CONCLUSION: Global expression analysis can identify expression patterns and individual genes that contribute to ovarian cancer development and outcome. Many of the genes that determine ovarian cancer survival are associated with the immune response, suggesting that immune function influences ovarian cancer virulence. With the generation of newer arrays with more transcripts, larger studies are possible to fully characterize genetic signatures that predict survival that may ultimately be used to guide therapeutic decision-making.

Authors
Lancaster, JM; Dressman, HK; Whitaker, RS; Havrilesky, L; Gray, J; Marks, JR; Nevins, JR; Berchuck, A
MLA Citation
Lancaster, JM, Dressman, HK, Whitaker, RS, Havrilesky, L, Gray, J, Marks, JR, Nevins, JR, and Berchuck, A. "Gene expression patterns that characterize advanced stage serous ovarian cancers." J Soc Gynecol Investig 11.1 (January 2004): 51-59.
PMID
14706684
Source
pubmed
Published In
Journal of the Society for Gynecologic Investigation (Elsevier)
Volume
11
Issue
1
Publish Date
2004
Start Page
51
End Page
59

Prediction of optimal versus suboptimal cytoreduction of advanced-stage serious ovarian cancer with the use of microarrays

Authors
Andrew, B; Iversen, ES; Lancaster, JM; Dressman, HK; West, M; Nevins, JR; Marks, JR; Miller, BE
MLA Citation
Andrew, B, Iversen, ES, Lancaster, JM, Dressman, HK, West, M, Nevins, JR, Marks, JR, and Miller, BE. "Prediction of optimal versus suboptimal cytoreduction of advanced-stage serious ovarian cancer with the use of microarrays." Women's Oncology Review 4.3 (2004): 203-204.
Source
scival
Published In
Women's Oncology Review
Volume
4
Issue
3
Publish Date
2004
Start Page
203
End Page
204
DOI
10.1080/14733400412331312585

Predictive models that combine multiple forms of genomic and clinical data to achieve personalized prediction of outcomes in breast cancer

Authors
Pittman, JL; Tebbit, CL; Black, EP; Dressman, HK; Huang, ES; Olson, JA; Marks, JR; Marcom, PK; Huang, AT; West, M; Nevins, JR
MLA Citation
Pittman, JL, Tebbit, CL, Black, EP, Dressman, HK, Huang, ES, Olson, JA, Marks, JR, Marcom, PK, Huang, AT, West, M, and Nevins, JR. "Predictive models that combine multiple forms of genomic and clinical data to achieve personalized prediction of outcomes in breast cancer." 2004.
Source
wos-lite
Published In
Breast Cancer Research and Treatment
Volume
88
Publish Date
2004
Start Page
S21
End Page
S22

Gene expression profiling can predict the extensive intraductal component phenotype in breast cancer.

Authors
Tebbit, CL; Marks, JR; Matthew, EJ; Eric, R; George, LS; Gretchen, M; Holly, D; Rex, B; Joseph, N; John, OA
MLA Citation
Tebbit, CL, Marks, JR, Matthew, EJ, Eric, R, George, LS, Gretchen, M, Holly, D, Rex, B, Joseph, N, and John, OA. "Gene expression profiling can predict the extensive intraductal component phenotype in breast cancer." 2004.
Source
wos-lite
Published In
Breast Cancer Research and Treatment
Volume
88
Publish Date
2004
Start Page
S112
End Page
S112

Progesterone receptor promoter+331/G/A polymorphism is associated with deceased risk of epithelial ovarian cancer.

Authors
Berchuck, A; Henriott, A; Wenham, RM; Calingaert, B; Ali, S; Rodriguez, GC; Marks, JR; Schildkraut, JM
MLA Citation
Berchuck, A, Henriott, A, Wenham, RM, Calingaert, B, Ali, S, Rodriguez, GC, Marks, JR, and Schildkraut, JM. "Progesterone receptor promoter+331/G/A polymorphism is associated with deceased risk of epithelial ovarian cancer." November 2003.
Source
wos-lite
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
12
Issue
11
Publish Date
2003
Start Page
1340S
End Page
1340S

Polymorphisms in BRCA1 and BRCA2 and risk of epithelial ovarian cancer.

PURPOSE: Because inherited BRCA1 or BRCA2 mutations strikingly increase ovarian cancer risk, polymorphisms in these genes could represent low penetrance susceptibility alleles. Previous studies of the BRCA2 N372H polymorphism suggested that HH homozygotes have a modestly increased risk of both breast and ovarian cancer. We have examined whether BRCA2 N372H or common amino acid-changing polymorphisms in BRCA1 predispose to ovarian cancer. EXPERIMENTAL DESIGN: A population-based, case control study of ovarian cancer was performed in North Carolina. Cases included 312 women with ovarian cancer (76% invasive and 24% borderline) and 401 age- and race-matched controls. Blood DNA from subjects was genotyped for BRCA2 N372H and BRCA1 Q356R and P871L. RESULTS: There was no association between BRCA2 N372H and risk of borderline or invasive epithelial ovarian cancer. The overall odds ratio (OR) for HH homozygotes was 0.8 [95% confidence interval (CI) = 0.4-1.5] and was similar in all subsets, including invasive serous cases. In addition, neither the BRCA1 Q356R (OR = 0.9, 95% CI 0.5-1.4) nor P871L (OR = 0.9, 95% CI 0.6-1.9) polymorphisms were associated with ovarian cancer risk. There was a significant racial difference in allele frequencies of the P871L polymorphism (P = 0.64 in Caucasians, L = 0.76 in African-Americans, P < 0.0001). CONCLUSIONS: In this population-based, case control study, common amino acid changing BRCA1 and 2 polymorphisms were not found to affect the risk of developing ovarian cancer.

Authors
Wenham, RM; Schildkraut, JM; McLean, K; Calingaert, B; Bentley, RC; Marks, J; Berchuck, A
MLA Citation
Wenham, RM, Schildkraut, JM, McLean, K, Calingaert, B, Bentley, RC, Marks, J, and Berchuck, A. "Polymorphisms in BRCA1 and BRCA2 and risk of epithelial ovarian cancer." Clin Cancer Res 9.12 (October 1, 2003): 4396-4403.
PMID
14555511
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
9
Issue
12
Publish Date
2003
Start Page
4396
End Page
4403

A neural survival factor is a candidate oncogene in breast cancer.

Using serial analysis of gene expression (SAGE), we identified a SAGE tag that was present only in invasive breast carcinomas and their lymph node metastases. The transcript corresponding to this SAGE tag, dermcidin (DCD), encodes a secreted protein normally expressed only in the pons of the brain and sweat glands. Array comparative genomic hybridization, fluorescence in situ hybridization, and immunohistochemical analyses determined that DCD is overexpressed in approximately 10% of invasive breast carcinomas; in some cases its overexpression is coupled with a focal copy number gain of its locus at 12q13.1, and its expression is associated with advanced clinical stage and poor prognosis. Expression of DCD in breast cancer cells promotes cell growth and survival and reduces serum dependency. Putative high- and low-affinity receptors for DCD are present on the cell surface of breast carcinomas and neurons of the brain. Based on these data we hypothesize that DCD may play a role in tumorigenesis by means of enhancing cell growth and survival in a subset of breast carcinomas.

Authors
Porter, D; Weremowicz, S; Chin, K; Seth, P; Keshaviah, A; Lahti-Domenici, J; Bae, YK; Monitto, CL; Merlos-Suarez, A; Chan, J; Hulette, CM; Richardson, A; Morton, CC; Marks, J; Duyao, M; Hruban, R; Gabrielson, E; Gelman, R; Polyak, K
MLA Citation
Porter, D, Weremowicz, S, Chin, K, Seth, P, Keshaviah, A, Lahti-Domenici, J, Bae, YK, Monitto, CL, Merlos-Suarez, A, Chan, J, Hulette, CM, Richardson, A, Morton, CC, Marks, J, Duyao, M, Hruban, R, Gabrielson, E, Gelman, R, and Polyak, K. "A neural survival factor is a candidate oncogene in breast cancer." Proc Natl Acad Sci U S A 100.19 (September 16, 2003): 10931-10936.
PMID
12953101
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
100
Issue
19
Publish Date
2003
Start Page
10931
End Page
10936
DOI
10.1073/pnas.1932980100

Matrix metalloproteinase-1 gene promoter polymorphism and risk of ovarian cancer.

OBJECTIVE: It has been suggested that the 2G allele of a guanine insertion-deletion promoter polymorphism in the promoter of the matrix metalloproteinase-1 (MMP1) gene may increase susceptibility to ovarian cancer. The 2G allele also has been associated with increased MMP1 expression. We investigated the relationship between the MMP1 polymorphism and ovarian cancer risk in a large population-based, case-control study. METHODS: The MMP1 promoter polymorphism was examined in white blood cell DNA from 311 cases and 387 age- and race-matched controls using a radiolabeled polymerase chain reaction assay. In addition, genotyping of the MMP1 polymorphism performed in 42 advanced-stage invasive serous ovarian cancers was compared to their mean relative MMP1 expression from Affymetrix microarrays. RESULTS: The 2G allele frequency did not differ significantly between cases (0.49) and controls (0.48), and the distribution of genotypes was in Hardy-Weinberg equilibrium. Using 1G homozygotes as the reference group, neither 2G homozygotes (odds ratio 1.1, 95% confidence interval 0.7-1.7) nor heterozygotes plus 2G homozygotes (odds ratio 0.9, 95% confidence interval 0.7-1.3) had an increased risk of ovarian cancer. There was also no relationship between MMP1 genotype and histologic grade, histologic type, stage, or tumor behavior (borderline versus invasive). The mean MMP1 expression was twice as high in 2G homozygotes relative to 1G homozygotes, but this difference was not statistically significant. CONCLUSION: The reported association between the MMP1 promoter polymorphism and ovarian cancer risk was not supported by our data. There was a suggestion that the 2G allele may be associated with higher MMP1 expression, and this finding is worthy of further investigation.

Authors
Wenham, RM; Calingaert, B; Ali, S; McClean, K; Whitaker, R; Bentley, R; Lancaster, JM; Schildkraut, J; Marks, J; Berchuck, A
MLA Citation
Wenham, RM, Calingaert, B, Ali, S, McClean, K, Whitaker, R, Bentley, R, Lancaster, JM, Schildkraut, J, Marks, J, and Berchuck, A. "Matrix metalloproteinase-1 gene promoter polymorphism and risk of ovarian cancer." J Soc Gynecol Investig 10.6 (September 2003): 381-387.
PMID
12969782
Source
pubmed
Published In
Journal of the Society for Gynecologic Investigation (Elsevier)
Volume
10
Issue
6
Publish Date
2003
Start Page
381
End Page
387

Neoadjuvant comparisons of aromatase inhibitors and tamoxifen: pretreatment determinants of response and on-treatment effect.

Adjuvant endocrine therapy reduces the risk of relapse and death from early stage hormone receptor positive breast cancer. However, tamoxifen is only partially effective because of the development of tumor resistance. Aromatase inhibitors (letrozole, anastrozole and exemestane) are also prone to the development of resistance but the pharmacologic action (estrogen deprivation) is distinct and so different mechanisms may be responsible. The problem of endocrine resistance can be directly studied in patients by examining the relationship between predictive tumor biomarkers and clinical outcome. In an example of a prospectively planned biomarker study, tumor samples were examined from a randomized trial of neoadjuvant endocrine treatment in which letrozole proved more effective than tamoxifen in terms of the rate of breast conservation and tumor regression. Interestingly letrozole was more effective at all levels of ER expression and was particularly more efficacious than tamoxifen for tumors that expressed HER1 and/or HER2 (with ER). This suggests that HER1/2 predicts primary tamoxifen resistance and relative sensitivity to potent estrogen deprivation, perhaps because HER1/2 signaling promotes the partial agonist effects of tamoxifen. A Phase 2 study of neoadjuvant letrozole is now underway to focus on gene expression profiling as a mechanism to further investigate the transcriptional programs that underlie resistance and sensitivity to estrogen deprivation. Expression profiles taken at baseline and after 1 month of therapy reveal dramatic reductions in the expression from genes responsible for DNA replication and synthesis, cell cycle progression, suppression of apoptosis and tissue invasion. When enough profiles have been generated it should be possible to detect complex interaction patterns that correctly reclassify ER+ disease into treatment responsive and resistant categories with high probability.

Authors
Ellis, MJ; Rosen, E; Dressman, H; Marks, J
MLA Citation
Ellis, MJ, Rosen, E, Dressman, H, and Marks, J. "Neoadjuvant comparisons of aromatase inhibitors and tamoxifen: pretreatment determinants of response and on-treatment effect." J Steroid Biochem Mol Biol 86.3-5 (September 2003): 301-307. (Review)
PMID
14623525
Source
pubmed
Published In
The Journal of Steroid Biochemistry and Molecular Biology
Volume
86
Issue
3-5
Publish Date
2003
Start Page
301
End Page
307

Dhh1 regulates the G1/S-checkpoint following DNA damage or BRCA1 expression in yeast.

BACKGROUND: Heterologous expression of the tumor suppressor BRCA1 in the yeast Saccharomyces cerevisiae is lethal. To identify potential new BRCA1-interacting gene targets, we characterized highly conserved ionizing radiation (IR) sensitive gene deletions that suppress BRCA1-induced lethality in yeast. MATERIALS AND METHODS: Previously, we exposed an isogenic collection of yeast strains individually deleted for 4746 nonessential genes to IR and identified 199 radiation sensitive deletion strains. A subset (n = 130) of these were screened for those that suppressed the G1 arrest and lethality observed following galactose-induced expression from a GAL::BRCA1 plasmid in wild type yeast. RESULTS: We found that deletions of two core components of the highly conserved CCR4-NOT transcription complex (CCR4 or DHH1) rescued BRCA1-induced G1 arrest and lethality in yeast. This was not because of down regulation of the GAL promoter since both deletion strains produce large amounts of BRCA1 that is rapidly degraded. In addition, heterologous expression of BRCA1 results in increased transcription of the DNA damage-inducible reporter construct DIN::LacZ. Reduced viability following IR and nitrogen starvation was observed among strains deleted for CCR4 or DHH1 because of a defect in G1 to S phase checkpoint transition. Lethality following nitrogen starvation and IR was partially rescued in dhh1Delta strains by expressing the human ortholog of DHH1 (DDX6) which has been identified as a breakpoint oncogene.T CONCLUSIONS: hese results suggest that BRCA1 may promote genomic stability in human cells by interacting with the highly conserved ortholog of DHH1 (DDX6) to properly activate G1/S checkpoint arrest following DNA damage.

Authors
Westmoreland, TJ; Olson, JA; Saito, WY; Huper, G; Marks, JR; Bennett, CB
MLA Citation
Westmoreland, TJ, Olson, JA, Saito, WY, Huper, G, Marks, JR, and Bennett, CB. "Dhh1 regulates the G1/S-checkpoint following DNA damage or BRCA1 expression in yeast." J Surg Res 113.1 (July 2003): 62-73.
PMID
12943812
Source
pubmed
Published In
Journal of Surgical Research
Volume
113
Issue
1
Publish Date
2003
Start Page
62
End Page
73

No relationship between ovarian cancer risk and progesterone receptor gene polymorphism in a population-based, case-control study in North Carolina.

Authors
Lancaster, JM; Wenham, RM; Halabi, S; Calingaert, B; Marks, JR; Moorman, PG; Bentley, RC; Berchuck, A; Schildkraut, JM
MLA Citation
Lancaster, JM, Wenham, RM, Halabi, S, Calingaert, B, Marks, JR, Moorman, PG, Bentley, RC, Berchuck, A, and Schildkraut, JM. "No relationship between ovarian cancer risk and progesterone receptor gene polymorphism in a population-based, case-control study in North Carolina." Cancer Epidemiol Biomarkers Prev 12.3 (March 2003): 226-227.
PMID
12646513
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
12
Issue
3
Publish Date
2003
Start Page
226
End Page
227

High expression of tumor necrosis factor-related apoptosis-inducing ligand is associated with favorable ovarian cancer survival.

PURPOSE: The molecular determinants of survival in ovarian cancer are poorly understood. Using expression microarrays, we recently found that high expression of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene is associated with prolonged survival in advanced ovarian cancer. TRAIL has also been shown to synergize with chemotherapeutic agents to induce apoptosis in ovarian cancer cell lines. We therefore sought to confirm the association between TRAIL expression and survival in a larger group of women with ovarian cancer. EXPERIMENTAL DESIGN: TRAIL expression was measured using quantitative real-time PCR in 120 epithelial ovarian cancers (11 stage I/II, 109 stage III/IV) and 8 normal ovarian surface epithelial samples. RESULTS: Ovarian cancers demonstrated 10-fold higher mean TRAIL expression than normal ovarian epithelial samples (P < 0.001). Among ovarian cancers, high TRAIL expression was associated with prolonged survival and was 2.2-fold higher in cancers from patients who lived more than 5 years compared with patients who died within 1 year (P = 0.03). CONCLUSIONS: TRAIL expression is higher in ovarian cancers relative to normal ovarian epithelium. High TRAIL expression is associated with favorable ovarian cancer survival, which may be attributable to increased chemosensitivity of cancers that express the most TRAIL. The use of TRAIL to enhance sensitivity of ovarian cancers to therapy represents an appealing molecular therapeutic strategy worthy of further investigation.

Authors
Lancaster, JM; Sayer, R; Blanchette, C; Calingaert, B; Whitaker, R; Schildkraut, J; Marks, J; Berchuck, A
MLA Citation
Lancaster, JM, Sayer, R, Blanchette, C, Calingaert, B, Whitaker, R, Schildkraut, J, Marks, J, and Berchuck, A. "High expression of tumor necrosis factor-related apoptosis-inducing ligand is associated with favorable ovarian cancer survival." Clin Cancer Res 9.2 (February 2003): 762-766.
PMID
12576447
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
9
Issue
2
Publish Date
2003
Start Page
762
End Page
766

Genomic amplification and oncogenic properties of the KCNK9 potassium channel gene

Representational difference analysis (RDA) of human breast cancer was used to discover a novel amplicon located at chromosomal region 8q24.3. We examined a series of breast cancer samples harboring amplification of this region and determined that KCNK9 is the sole overexpressed gene within the amplification epicenter. KCNK9 encodes a potassium channel that is amplified from 3-fold to 10-fold in 10% of breast tumors and overexpressed from 5-fold to over 100-fold in 44% of breast tumors. Overexpression of KCNK9 in cell lines promotes tumor formation and confers resistance to both hypoxia and serum deprivation, suggesting that its amplification and overexpression plays a physiologically important role in human breast cancer.

Authors
Mu, D; Chen, L; Zhang, X; See, L-H; Koch, CM; Yen, C; Tong, JJ; Spiegel, L; Nguyen, KCQ; Servoss, A; Peng, Y; Pei, L; Marks, JR; Lowe, S; Hoey, T; Jan, LY; McCombie, WR; Wigler, MH; Powers, S
MLA Citation
Mu, D, Chen, L, Zhang, X, See, L-H, Koch, CM, Yen, C, Tong, JJ, Spiegel, L, Nguyen, KCQ, Servoss, A, Peng, Y, Pei, L, Marks, JR, Lowe, S, Hoey, T, Jan, LY, McCombie, WR, Wigler, MH, and Powers, S. "Genomic amplification and oncogenic properties of the KCNK9 potassium channel gene." Cancer Cell 3.3 (2003): 297-302.
PMID
12676587
Source
scival
Published In
Cancer Cell
Volume
3
Issue
3
Publish Date
2003
Start Page
297
End Page
302
DOI
10.1016/S1535-6108(03)00054-0

Molecular markers in ductal carcinoma in situ of the breast

Gene expression patterns in ductal carcinoma in situ (DCIS), and in invasive, and metastatic breast tumors were determined using serial analysis of gene expression (SAGE). We used mRNA in situ hybridization to examine gene expression at the cellular level and immunohistochemistry on tissue microarrays to determine association between gene expression patterns and histopathologic characteristics of the tumors. We found that that the most dramatic transcriptome change occurs at the normal to DCIS transition, while there is no clear universal "in situ" or "invasive" tumor molecular signature. From the 16,430 transcripts analyzed, we identified only 5 and 11 that were preferentially up-regulated in DCIS and invasive tumors, respectively. The majority of invasive cancer specific SAGE tags correspond to novel genes. The genes we identified may define biologically and clinically meaningful subgroups of DCIS with a high risk of progression to invasive disease.

Authors
Porter, D; Lahti-Domenici, J; Keshaviah, A; Bae, YK; Argani, P; Marks, J; Richardson, A; Cooper, A; Strausberg, R; Riggins, GJ; Schnitt, S; Gabrielson, E; Gelman, R; Polyak, K
MLA Citation
Porter, D, Lahti-Domenici, J, Keshaviah, A, Bae, YK, Argani, P, Marks, J, Richardson, A, Cooper, A, Strausberg, R, Riggins, GJ, Schnitt, S, Gabrielson, E, Gelman, R, and Polyak, K. "Molecular markers in ductal carcinoma in situ of the breast." Molecular Cancer Research 1.5 (2003): 362-375.
PMID
12651909
Source
scival
Published In
Molecular Cancer Research
Volume
1
Issue
5
Publish Date
2003
Start Page
362
End Page
375

Development of a novel tissue acquisition protocol for biomarker studies in early stage breast cancer.

Authors
Tebbit, CL; Ellis, M; Marks, JR; Bentley, RC; Mann, G; Soo, MS; Rosen, E; Baker, J; Leight, G; Olson, JA
MLA Citation
Tebbit, CL, Ellis, M, Marks, JR, Bentley, RC, Mann, G, Soo, MS, Rosen, E, Baker, J, Leight, G, and Olson, JA. "Development of a novel tissue acquisition protocol for biomarker studies in early stage breast cancer." 2003.
Source
wos-lite
Published In
Breast Cancer Research and Treatment
Volume
82
Publish Date
2003
Start Page
S143
End Page
S144

MTA-1 (metastasis associated protein-1) is upregulated in tamoxifen-resistant breast cancer

Authors
Blackwell, KL; Dewhirst, MW; McDonnell, DP; Dressman, H; Snyder, SA; Marks, JR
MLA Citation
Blackwell, KL, Dewhirst, MW, McDonnell, DP, Dressman, H, Snyder, SA, and Marks, JR. "MTA-1 (metastasis associated protein-1) is upregulated in tamoxifen-resistant breast cancer." 2003.
Source
wos-lite
Published In
Breast Cancer Research and Treatment
Volume
82
Publish Date
2003
Start Page
S88
End Page
S88

BRCA2 monoclonal antibodies react with differentiating epithelium.

The BRCA2 gene has previously been suggested to play a role in proliferation and DNA repair. Germline mutations in the BRCA2 gene predispose individuals to early onset, hereditary breast cancer. To better understand the expression pattern and function of the BRCA2 gene product, we have developed immunological reagents specific for BRCA2. These reagents recognize full-length (384 kDa) recombinant human BRCA2 proteins in transfected cell lysates as well as multiple smaller recombinant BRCA2 polypeptides. Detection of native BRCA2 protein in most tissue types, including breast epithelium, requires sensitive techniques such as immunoprecipitation-Western blot analysis. However, we have demonstrated strong reactivity of our immunological reagents with differentiating epithelium, including epidermis, thymic epithelium, and squamous cell carcinoma. These data suggest that BRCA2 may play a role in processes associated with cellular differentiation, in addition to its previously suggested roles in proliferation and DNA repair.

Authors
Gilliam, LK; Lobenhofer, EK; Greer, PK; Scearce, RM; Cirisano, FD; Marks, JR; Hale, LP
MLA Citation
Gilliam, LK, Lobenhofer, EK, Greer, PK, Scearce, RM, Cirisano, FD, Marks, JR, and Hale, LP. "BRCA2 monoclonal antibodies react with differentiating epithelium." Hybrid Hybridomics 21.4 (August 2002): 261-269.
PMID
12193279
Source
pubmed
Published In
Hybridoma and Hybridomics
Volume
21
Issue
4
Publish Date
2002
Start Page
261
End Page
269
DOI
10.1089/153685902760213877

Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23.

We found that PPM1D, encoding a serine/threonine protein phosphatase, lies within an epicenter of the region at 17q23 that is amplified in breast cancer. We show that overexpression of this gene confers two oncogenic phenotypes on cells in culture: attenuation of apoptosis induced by serum starvation and transformation of primary cells in cooperation with RAS.

Authors
Li, J; Yang, Y; Peng, Y; Austin, RJ; van Eyndhoven, WG; Nguyen, KCQ; Gabriele, T; McCurrach, ME; Marks, JR; Hoey, T; Lowe, SW; Powers, S
MLA Citation
Li, J, Yang, Y, Peng, Y, Austin, RJ, van Eyndhoven, WG, Nguyen, KCQ, Gabriele, T, McCurrach, ME, Marks, JR, Hoey, T, Lowe, SW, and Powers, S. "Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23." Nat Genet 31.2 (June 2002): 133-134.
PMID
12021784
Source
pubmed
Published In
Nature Genetics
Volume
31
Issue
2
Publish Date
2002
Start Page
133
End Page
134
DOI
10.1038/ng888

Prediction and uncertainty in the analysis of gene expression profiles.

We have developed a complete statistical model for the analysis of tumor specific gene expression profiles. The approach provides investigators with a global overview on large scale gene expression data, indicating aspects of the data that relate to tumor phenotype, but also summarizing the uncertainties inherent in classification of tumor types. We demonstrate the use of this method in the context of a gene expression profiling study of 27 human breast cancers. The study is aimed at defining molecular characteristics of tumors that reflect estrogen receptor tatus. In addition to good predictive performance with respect to pure classification of the expression profiles, the model also uncovers conflicts in the data with respect to the classification of some of the tumors, highlighting them as critical cases for which additional investigations are appropriate.

Authors
Spang, R; Zuzan, H; West, M; Nevins, J; Blanchette, C; Marks, JR
MLA Citation
Spang, R, Zuzan, H, West, M, Nevins, J, Blanchette, C, and Marks, JR. "Prediction and uncertainty in the analysis of gene expression profiles." In Silico Biol 2.3 (2002): 369-381.
PMID
12542420
Source
pubmed
Published In
In silico biology
Volume
2
Issue
3
Publish Date
2002
Start Page
369
End Page
381

Loss of expression of the p16 tumor suppressor gene is more frequent in advanced ovarian cancers lacking p53 mutations.

OBJECTIVE: The aim of this study was to test the hypothesis that p53 mutations are less frequent in ovarian cancers with alterations in other genes that regulate G1 progression. METHODS: Expression of G1 stimulatory (cyclins D1 and E, cdk4, Ki67) and inhibitory (p16, Rb, p27, p14) genes was analyzed using Western blots in 84 primary ovarian cancers and seven cell lines of known p53 mutation status. Expression of p16 and Rb also was determined using immunohistochemistry and the p16 gene was examined for homozygous deletions and mutations. RESULTS: Loss of p16 protein was more frequent in ovarian cancers with wild-type p53. All four cell lines with wild-type p53 had lost p16 compared to only one of three with mutant p53 genes. p16 expression was absent in 34% (28/82) of primary ovarian cancers, and this was significantly more common in cases with wild-type p53 (14/28, 50%) compared to those with p53 mutations (14/54, 26%, P = 0.03). Homozygous deletion of the p16 gene was found in cell lines lacking p16, but not in any primary cancers. p16 loss was more common in serous (21/52, 40%) than nonserous cancers (4/23, 17%, P = 0.07). Cases that expressed p16 were more likely to express high levels of Rb (47/55, 85%) than p16-negative cases (12/28, 43%, P < 0.001). Loss of Rb occurred in 5/30 (17%) ovarian cancers lacking p53 mutations compared to 5/54 (9%) cases with p53 mutations (P = 0.48). Expression of G1 stimulatory proteins (cyclins D1 and E, cdk4, Ki67) did not correlate with p53 mutation status. CONCLUSIONS: Loss of expression of the p16 tumor suppressor occurs more often in ovarian cancers lacking p53 mutations. These data are consistent with the paradigm that inactivation of p53 is less of a requisite event in ovarian carcinogenesis when another G1 regulatory gene such as p16 already has been inactivated.

Authors
Havrilesky, LJ; Alvarez, AA; Whitaker, RS; Marks, JR; Berchuck, A
MLA Citation
Havrilesky, LJ, Alvarez, AA, Whitaker, RS, Marks, JR, and Berchuck, A. "Loss of expression of the p16 tumor suppressor gene is more frequent in advanced ovarian cancers lacking p53 mutations." Gynecol Oncol 83.3 (December 2001): 491-500.
PMID
11733961
Source
pubmed
Published In
Gynecologic Oncology
Volume
83
Issue
3
Publish Date
2001
Start Page
491
End Page
500
DOI
10.1006/gyno.2001.6464

Evaluation of new expression-based markers for detection of breast cancer cells.

Authors
Marks, JR; Brown, NM; Stenzel, TT; Roberts, L; Henslee, J; Friedman, P
MLA Citation
Marks, JR, Brown, NM, Stenzel, TT, Roberts, L, Henslee, J, and Friedman, P. "Evaluation of new expression-based markers for detection of breast cancer cells." November 2001.
Source
wos-lite
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
7
Issue
11
Publish Date
2001
Start Page
3688S
End Page
3688S

Predicting the clinical status of human breast cancer by using gene expression profiles.

Prognostic and predictive factors are indispensable tools in the treatment of patients with neoplastic disease. For the most part, such factors rely on a few specific cell surface, histological, or gross pathologic features. Gene expression assays have the potential to supplement what were previously a few distinct features with many thousands of features. We have developed Bayesian regression models that provide predictive capability based on gene expression data derived from DNA microarray analysis of a series of primary breast cancer samples. These patterns have the capacity to discriminate breast tumors on the basis of estrogen receptor status and also on the categorized lymph node status. Importantly, we assess the utility and validity of such models in predicting the status of tumors in crossvalidation determinations. The practical value of such approaches relies on the ability not only to assess relative probabilities of clinical outcomes for future samples but also to provide an honest assessment of the uncertainties associated with such predictive classifications on the basis of the selection of gene subsets for each validation analysis. This latter point is of critical importance in the ability to apply these methodologies to clinical assessment of tumor phenotype.

Authors
West, M; Blanchette, C; Dressman, H; Huang, E; Ishida, S; Spang, R; Zuzan, H; Olson, JA; Marks, JR; Nevins, JR
MLA Citation
West, M, Blanchette, C, Dressman, H, Huang, E, Ishida, S, Spang, R, Zuzan, H, Olson, JA, Marks, JR, and Nevins, JR. "Predicting the clinical status of human breast cancer by using gene expression profiles." Proc Natl Acad Sci U S A 98.20 (September 25, 2001): 11462-11467.
PMID
11562467
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
98
Issue
20
Publish Date
2001
Start Page
11462
End Page
11467
DOI
10.1073/pnas.201162998

HIN-1, a putative cytokine highly expressed in normal but not cancerous mammary epithelial cells.

To identify molecular alterations implicated in the initiating steps of breast tumorogenesis, we compared the gene expression profiles of normal and ductal carcinoma in situ (DCIS) mammary epithelial cells by using serial analysis of gene expression (SAGE). Through the pair-wise comparison of normal and DCIS SAGE libraries, we identified several differentially expressed genes. Here, we report the characterization of one of these genes, HIN-1 (high in normal-1). HIN-1 expression is significantly down regulated in 94% of human breast carcinomas and in 95% of preinvasive lesions, such as ductal and lobular carcinoma in situ. This decrease in HIN-1 expression is accompanied by hypermethylation of its promoter in the majority of breast cancer cell lines (>90%) and primary tumors (74%). HIN-1 is a putative cytokine with no significant homology to known proteins. Reintroduction of HIN-1 into breast cancer cells inhibits cell growth. These results indicate that HIN-1 is a candidate tumor suppressor gene that is inactivated at high frequency in the earliest stages of breast tumorogenesis.

Authors
Krop, IE; Sgroi, D; Porter, DA; Lunetta, KL; LeVangie, R; Seth, P; Kaelin, CM; Rhei, E; Bosenberg, M; Schnitt, S; Marks, JR; Pagon, Z; Belina, D; Razumovic, J; Polyak, K
MLA Citation
Krop, IE, Sgroi, D, Porter, DA, Lunetta, KL, LeVangie, R, Seth, P, Kaelin, CM, Rhei, E, Bosenberg, M, Schnitt, S, Marks, JR, Pagon, Z, Belina, D, Razumovic, J, and Polyak, K. "HIN-1, a putative cytokine highly expressed in normal but not cancerous mammary epithelial cells." Proc Natl Acad Sci U S A 98.17 (August 14, 2001): 9796-9801.
PMID
11481438
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
98
Issue
17
Publish Date
2001
Start Page
9796
End Page
9801
DOI
10.1073/pnas.171138398

A SAGE (serial analysis of gene expression) view of breast tumor progression.

To identify molecular alterations involved in the initiation and progression of breast carcinomas, we analyzed the global gene expression profiles of normal mammary epithelial cells and in situ, invasive, and metastatic breast carcinomas using serial analysis of gene expression (SAGE). We identified sets of genes expressed only or most abundantly in a specific stage of breast tumorigenesis or in a certain subtype of tumors through the pair-wise comparison and by hierarchical clustering analysis of these eight SAGE libraries (two/stage). On the basis of these comparisons, we made the following observations: Normal mammary epithelial cells showed the most distinct and least variable gene expression profiles. Many of the genes highly expressed in normal mammary epithelium and lost in carcinomas encoded secreted proteins, cytokines, and chemokines, implicating abnormal paracrine and autocrine signaling in the initiation of breast tumorigenesis. Very few genes were universally up-regulated in all tumors regardless of their stage and histological grade, indicating a high degree of diversity at the molecular level that likely reflects the clinical heterogeneity characteristic of breast carcinomas. Tumors of different histology type and stage had very distinct gene expression patterns. No genes seemed to be specific for metastatic or for in situ carcinomas. We found that the most dramatic and consistent phenotypic change occurred at the normal-to-in situ carcinoma transition. This observation, combined with the fact that many of the genes involved encode secreted, cell-nonautonomous factors, implies that the normal epithelium-to-in situ carcinoma transition may be the most promising target for cancer prevention and treatment.

Authors
Porter, DA; Krop, IE; Nasser, S; Sgroi, D; Kaelin, CM; Marks, JR; Riggins, G; Polyak, K
MLA Citation
Porter, DA, Krop, IE, Nasser, S, Sgroi, D, Kaelin, CM, Marks, JR, Riggins, G, and Polyak, K. "A SAGE (serial analysis of gene expression) view of breast tumor progression." Cancer Res 61.15 (August 1, 2001): 5697-5702.
PMID
11479200
Source
pubmed
Published In
Cancer Research
Volume
61
Issue
15
Publish Date
2001
Start Page
5697
End Page
5702

Prognostic significance of the number of lymph nodes examined in patients with lymph node-negative breast carcinoma.

BACKGROUND: A recent report suggested that the number of lymph nodes examined was a strong predictor of survival in patients with lymph node-negative breast carcinoma. Among women who had >or= 20 lymph nodes examined, the risk of dying from breast carcinoma within 5 years was increased nearly 4-fold compared with women who had fewer lymph nodes examined. Because these findings were based on a relatively small cohort of patients, corroborative studies with larger patient populations were needed. METHODS: The authors studied the relation between the number of lymph nodes examined and breast carcinoma survival among 911 women with lymph node-negative breast carcinoma with a median length of follow-up of 84 months. The association between other prognostic indicators and survival and the number of lymph nodes examined also was investigated. RESULTS: The number of lymph nodes examined was not found to be associated with either 5-year or long-term survival. The proportion of women dying from breast carcinoma was the same (8%) in both groups (those patients with >or= 20 lymph nodes examined vs. those in whom < 20 lymph nodes were examined) and the hazard ratio was 0.98 (95% confidence interval, 0.58-1.64). CONCLUSIONS: In this larger study population, the authors failed to confirm the findings of an earlier investigation in which having a larger number of lymph nodes examined was associated with poorer survival. This finding suggests that it is unlikely the number of lymph nodes examined is an important prognostic indicator in patients with lymph node-negative breast carcinoma.

Authors
Moorman, PG; Hamza, A; Marks, JR; Olson, JA
MLA Citation
Moorman, PG, Hamza, A, Marks, JR, and Olson, JA. "Prognostic significance of the number of lymph nodes examined in patients with lymph node-negative breast carcinoma." Cancer 91.12 (June 15, 2001): 2258-2262.
PMID
11413513
Source
pubmed
Published In
Cancer
Volume
91
Issue
12
Publish Date
2001
Start Page
2258
End Page
2262

Relationship between expression of coactivators and corepressors of hormone receptors and resistance of ovarian cancers to growth regulation by steroid hormones.

OBJECTIVE: To determine whether aberrant expression of hormone receptor corepressors or coactivators or defects in estrogen receptor-mediated transcription might underlie resistance of ovarian cancers to hormonal therapy. METHODS: Northern analysis, Western analysis, and polymerase chain reaction were used to examine expression of estrogen receptor (ER), progesterone receptor (PR), the nuclear receptor corepressors N-CoR and SMRT, and the steroid receptor coactivator BRG-1 in ovarian cancer cell lines and primary cancers. The effect of BRG-1 transfection on ER-mediated transcription was examined. We also determined the effect of estrogen and the pure estrogen antagonist ICI 182,780 on cell cycle profile and expression of ER. Finally, we examined the ability of estrogen to upregulate expression of known estrogen-responsive genes. RESULTS: Among primary ovarian cancers, 18 of 52 (35%) expressed N-CoR, and 37 of 52 (71%) expressed SMRT, but there was no correlation between expression of corepressors and hormone receptor status. All of the primary ovarian cancers and cell lines expressed BRG-1. Estrogen stimulation of two cell lines expressing ER (SKOV3, OVCA 432) elicited low levels of ER-mediated transcription that was not enhanced by BRG-1 transfection. ICI 182,780 did not induce cell cycle arrest in these cell lines, but there was evidence of downregulation of ER, indicating a ligand-receptor interaction. However, estrogen did not elicit increased transcription of estrogen-responsive genes (PR, myc, fos, pS2). CONCLUSION: Inappropriate expression of the nuclear corepressors N-CoR and SMRT or the coactivator BRG-1 does not underlie the resistance of ovarian cancers to hormonal therapy. Further studies are needed to elucidate the mechanisms underlying the inability of ovarian cancers to undergo ER-mediated transcription if we hope to understand their resistance to hormonal therapy.

Authors
Havrilesky, LJ; McMahon, CP; Lobenhofer, EK; Whitaker, R; Marks, JR; Berchuck, A
MLA Citation
Havrilesky, LJ, McMahon, CP, Lobenhofer, EK, Whitaker, R, Marks, JR, and Berchuck, A. "Relationship between expression of coactivators and corepressors of hormone receptors and resistance of ovarian cancers to growth regulation by steroid hormones." J Soc Gynecol Investig 8.2 (March 2001): 104-113.
PMID
11336882
Source
pubmed
Published In
Journal of the Society for Gynecologic Investigation (Elsevier)
Volume
8
Issue
2
Publish Date
2001
Start Page
104
End Page
113

Loss of cyclin D2 expression in the majority of breast cancers is associated with promoter hypermethylation

Cyclin D2 is a member of the D-type cyclins, implicated in cell cycle regulation, differentiation, and malignant transformation. It was noted previously that cyclin D2 is not expressed in the majority of breast cancer cell lines, whereas abundant expression was detected in finite life span human mammary epithelial cells. By reverse transcription-PCR and Western blot analysis, we extended this finding to primary breast carcinomas and show that the majority of these tumors lack expression of cyclin D2 mRNA (18 of 24) and protein (10 of 13). In contrast, both luminal and myoepithelial subpopulations of normal breast tissues expressed cyclin D2. Hypermethylation of the CpG island in the promoter was detected by methylation-specific PCR in nearly half of the breast cancers (49 of 106) and was associated with silencing of cyclin D2 gene expression. Promoter hypermethylation was also detected in ductal carcinoma in situ, suggesting that loss of cyclin D2 expression is an early event in tumorigenesis. Our results suggest that loss of cyclin D2 expression is associated with the evolution of breast cancer.

Authors
Evron, E; Umbricht, CB; Korz, D; Raman, V; Loeb, DM; Niranjan, B; Buluwela, L; Weitzman, SA; Marks, J; Sukumar, S
MLA Citation
Evron, E, Umbricht, CB, Korz, D, Raman, V, Loeb, DM, Niranjan, B, Buluwela, L, Weitzman, SA, Marks, J, and Sukumar, S. "Loss of cyclin D2 expression in the majority of breast cancers is associated with promoter hypermethylation." Cancer Research 61.6 (2001): 2782-2787.
PMID
11289162
Source
scival
Published In
Cancer Research
Volume
61
Issue
6
Publish Date
2001
Start Page
2782
End Page
2787

Hypermethylation of 14-3-3 σ (stratifin) is an early event in breast cancer

We have identified 14-3-3 σ (σ) as a gene whose expression is lost in breast carcinomas, primarily by methylation-mediated silencing. In this report, we investigated the timing of loss of σ gene expression during breast tumorigenesis in vivo. We analysed the methylation status of σ in breast cancer precursor lesions using microdissection for selective tissue sampling. We found hypermethylation of σ in 24 of 25 carcinomas (96%), 15 of 18 (83%) of ductal carcinoma in situ, and three of eight (38%) of atypical hyperplasias. None of the five hyperplasias without atypia showed σ-hypermethylation. Unexpectedly, patients with breast cancer showed σ hypermethylation in adjacent histologically normal breast epithelium, while this was never observed in individuals without evidence of breast cancer. Also, samples of periductal stromal breast tissue were consistently hypermethylated, underscoring the importance of selective tissue sampling for accurate assessment of 14-3-3-σ methylation in breast epithelium. These results suggest that hypermethylation of 14-3-3-σ occurs at an early stage in the progression to invasive breast cancer, and may occur in apparently normal epithelium adjacent to breast cancer. These results provide evidence that loss of expression of σ is an early event in neoplastic transformation.

Authors
Umbricht, CB; Evron, E; Gabrielson, E; Ferguson, A; Marks, J; Sukumar, S
MLA Citation
Umbricht, CB, Evron, E, Gabrielson, E, Ferguson, A, Marks, J, and Sukumar, S. "Hypermethylation of 14-3-3 σ (stratifin) is an early event in breast cancer." Oncogene 20.26 (2001): 3348-3353.
PMID
11423985
Source
scival
Published In
Oncogene: Including Oncogene Reviews
Volume
20
Issue
26
Publish Date
2001
Start Page
3348
End Page
3353
DOI
10.1038/sj.onc.1204438

Phenol sulfotransferases: hormonal regulation, polymorphism, and age of onset of breast cancer.

In recent years, significant effort has been made to identify genes that influence breast cancer risk. Because the high-penetrance breast cancer susceptibility genes BRCA1 and 2 play a role only in a small fraction of breast cancer cases, understanding the genetic risk of the majority of breast cancers will require the identification and analysis of several lower penetrance genes. The estrogen-signaling pathway plays a crucial role in the pathophysiology of breast cancer; therefore, polymorphism in genes involved in this pathway is likely to influence breast cancer risk. Our detailed analysis of gene expression profiles of estrogen- and 4-OH-tamoxifen-treated ZR75-1 breast cancer cells identified members of the sulfotransferase 1A (SULT1A) phenol sulfotransferase family as downstream targets of tamoxifen. On the basis of the induction of SULT1A by 4-OH-tamoxifen and the known inherited variability in SULT1A enzymatic activity, we hypothesized that polymorphism in sulfotransferase genes might influence the risk of breast cancer. Using an RFLP that distinguishes an arginine to histidine change in exon 7 of the SULT1A1 gene, we characterized SULT1A1 genotypes in relation to breast cancer risk. An analysis of 444 breast cancer patients and 227 controls revealed no effect of SULT1A1 genotype on the risk of breast cancer (P = 0.69); however, it did appear to influence the age of onset among early-onset affected patients (P = 0.04). Moreover, individuals with the higher activity SULT1A1*1 allele were more likely to have other tumors in addition to breast cancer (P = 0.004; odds ratio, 3.02; 95% confidence interval, 1.32, 8.09). The large number of environmental mutagens and carcinogens activated by sulfotransferases and the high frequency of the SULT1A1*1 allele in human populations warrants additional studies to address the role of SULT genes in human cancer.

Authors
Seth, P; Lunetta, KL; Bell, DW; Gray, H; Nasser, SM; Rhei, E; Kaelin, CM; Iglehart, DJ; Marks, JR; Garber, JE; Haber, DA; Polyak, K
MLA Citation
Seth, P, Lunetta, KL, Bell, DW, Gray, H, Nasser, SM, Rhei, E, Kaelin, CM, Iglehart, DJ, Marks, JR, Garber, JE, Haber, DA, and Polyak, K. "Phenol sulfotransferases: hormonal regulation, polymorphism, and age of onset of breast cancer." Cancer Res 60.24 (December 15, 2000): 6859-6863.
PMID
11156380
Source
pubmed
Published In
Cancer Research
Volume
60
Issue
24
Publish Date
2000
Start Page
6859
End Page
6863

Estrogen-induced mitogenesis of MCF-7 cells does not require the induction of mitogen-activated protein kinase activity.

Estrogen mediates the transcription of responsive genes via its interaction with the estrogen receptor (ER). This ligand-dependent transcriptional activity has been the mechanistic basis for understanding estrogen-induced proliferation. However, recent reports suggest that estrogen stimulation results in activation of the mitogen-activated protein kinase (MAPK) cascade in an ER-dependent manner suggesting that mitogenesis may be mediated through this cytoplasmic signaling cascade. In this study, we demonstrate that estrogen stimulation of MCF-7 cells does not activate MAPK regardless of hormone concentration, serum concentration, or cell density. We also excluded the activation of MAPK through autocrine effects after estrogen treatment. Finally, concentrations required for estrogen-induced mitogenesis and estrogen-mediated transcription were shown to be the same. These results support transcriptional activation as the primary mechanism for estrogen-mediated mitogenesis.

Authors
Lobenhofer, EK; Marks, JR
MLA Citation
Lobenhofer, EK, and Marks, JR. "Estrogen-induced mitogenesis of MCF-7 cells does not require the induction of mitogen-activated protein kinase activity." J Steroid Biochem Mol Biol 75.1 (December 1, 2000): 11-20.
PMID
11179904
Source
pubmed
Published In
The Journal of Steroid Biochemistry and Molecular Biology
Volume
75
Issue
1
Publish Date
2000
Start Page
11
End Page
20

BRCA1 copy number in paraffin embedded cancer tissue samples of known BRCA1 and BRCA2 mutation carriers using a BRCA1 FISH probe.

Authors
Young, SR; Kataoka, N; Wang, Z; Kato, H; Loging, WT; Marks, JR; Lehman, N
MLA Citation
Young, SR, Kataoka, N, Wang, Z, Kato, H, Loging, WT, Marks, JR, and Lehman, N. "BRCA1 copy number in paraffin embedded cancer tissue samples of known BRCA1 and BRCA2 mutation carriers using a BRCA1 FISH probe." October 2000.
Source
wos-lite
Published In
The American Journal of Human Genetics
Volume
67
Issue
4
Publish Date
2000
Start Page
74
End Page
74

High frequency of hypermethylation at the 14-3-3 sigma locus leads to gene silencing in breast cancer.

Expression of 14-3-3 final sigma (final sigma) is induced in response to DNA damage, and causes cells to arrest in G(2). By SAGE (serial analysis of gene expression) analysis, we identified final sigma as a gene whose expression is 7-fold lower in breast carcinoma cells than in normal breast epithelium. We verified this finding by Northern blot analysis. Remarkably, final sigma mRNA was undetectable in 45 of 48 primary breast carcinomas. Genetic alterations at final sigma such as loss of heterozygosity were rare (1/20 informative cases), and no mutations were detected (0/34). On the other hand, hypermethylation of CpG islands in the final sigma gene was detected in 91% (75/82) of breast tumors and was associated with lack of gene expression. Hypermethylation of final sigma is functionally important, because treatment of final sigma-non-expressing breast cancer cell lines with the drug 5-aza-2'-deoxycytidine resulted in demethylation of the gene and synthesis of final sigma mRNA. Breast cancer cells lacking final sigma expression showed increased number of chromosomal breaks and gaps when exposed to gamma-irradiation. Therefore, it is possible that loss of final sigma expression contributes to malignant transformation by impairing the G(2) cell cycle checkpoint function, thus allowing an accumulation of genetic defects. Hypermethylation and loss of final sigma expression are the most consistent molecular alterations in breast cancer identified so far.

Authors
Ferguson, AT; Evron, E; Umbricht, CB; Pandita, TK; Chan, TA; Hermeking, H; Marks, JR; Lambers, AR; Futreal, PA; Stampfer, MR; Sukumar, S
MLA Citation
Ferguson, AT, Evron, E, Umbricht, CB, Pandita, TK, Chan, TA, Hermeking, H, Marks, JR, Lambers, AR, Futreal, PA, Stampfer, MR, and Sukumar, S. "High frequency of hypermethylation at the 14-3-3 sigma locus leads to gene silencing in breast cancer." Proc Natl Acad Sci U S A 97.11 (May 23, 2000): 6049-6054.
PMID
10811911
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
97
Issue
11
Publish Date
2000
Start Page
6049
End Page
6054
DOI
10.1073/pnas.100566997

Inhibition of mitogen-activated protein kinase and phosphatidylinositol 3-kinase activity in MCF-7 cells prevents estrogen-induced mitogenesis.

Estrogen acts to promote DNA synthesis in the MCF-7 human breast cancer cell line via its interaction with high levels of estrogen receptor. The primary mode of estrogen action has been considered to be through transcriptional activation of genes containing estrogen response elements, including the immediate early genes c-myc and fos. Recent reports have indicated that estrogen, acting through the estrogen receptor, is capable of inducing the mitogen-activated protein kinase (MAPK) cytoplasmic signaling cascade. In this study, specific small molecule inhibitors of MAPK and phosphatidylinositol 3-kinase activity were used to determine the influence of these cascades on estrogen-mediated mitogenesis. Phosphatidylinositol 3-kinase inhibitors, LY294002 and wortmannin, as well as inhibitors of MAPK kinase-1, PD098059 and U0126, decreased the fraction of cells entering DNA synthesis after treatment with 17beta-estradiol. These compounds did not inhibit expression of myc or fos. However, the drugs did prevent the accumulation of cyclin D1 and hyperphosphorylated retinoblastoma protein, indicating that the block occurred at, or prior to, this point in the cell cycle. Although these compounds were effective in preventing estrogen-mediated mitogenesis, the downstream kinases extracellular signal-regulated kinase 1, extracellular signal-regulated kinase 2, and protein kinase B were not activated over basal levels by estrogen treatment. These studies suggest that estrogen initiates mitogenesis by inducing the transcription of immediate early genes, but cytoplasmic signaling pathways play an important role in the control of subsequent events in the cell cycle.

Authors
Lobenhofer, EK; Huper, G; Iglehart, JD; Marks, JR
MLA Citation
Lobenhofer, EK, Huper, G, Iglehart, JD, and Marks, JR. "Inhibition of mitogen-activated protein kinase and phosphatidylinositol 3-kinase activity in MCF-7 cells prevents estrogen-induced mitogenesis." Cell Growth Differ 11.2 (February 2000): 99-110.
PMID
10714766
Source
pubmed
Published In
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research
Volume
11
Issue
2
Publish Date
2000
Start Page
99
End Page
110

Compromised HOXA5 function can limit p53 expression in human breast tumours

Expression of the p55 gene protects cells against malignant transformation. Whereas control of p53 degradation has been a subject of intense scrutiny, little is known about the factors that regulate p53 synthesis. Here we show that p53 messenger RNA levels are low in a large proportion of breast tumours. Seeking potential regulators of p53 transcription, we found consensus HOX binding sites in the p53 promoter. Transient transfection of Hox/HOXA5 activated the p53 promoter. Expression of HOXA5 in epithelial cancer cells expressing wild-type p53, but not in isogenic variants lacking the p53 gene, led to apoptotic cell death. Moreover, breast cancer cell lines and patient tumours display a coordinate loss of p53 and HOXA5 mRNA and protein expression. The HOXA5 promoter region was methylated in 16 out of 20 p53-negative breast tumour specimens. We conclude that loss of expression of p53 in human breast cancer may be primarily due to lack of expression of HOXA5.

Authors
Raman, V; Martenser, SA; Reisman, D; Evron, E; Odenwald, WF; Jaffee, E; Marks, J; Sukumar, S
MLA Citation
Raman, V, Martenser, SA, Reisman, D, Evron, E, Odenwald, WF, Jaffee, E, Marks, J, and Sukumar, S. "Compromised HOXA5 function can limit p53 expression in human breast tumours." Nature 405.6789 (2000): 974-978.
PMID
10879542
Source
scival
Published In
Nature
Volume
405
Issue
6789
Publish Date
2000
Start Page
974
End Page
978
DOI
10.1038/35016125

Managing hereditary ovarian cancer risk.

Ovarian cancer is the fourth leading cause of cancer deaths in American women. About 10% of cases are thought to have a hereditary basis, and family history is the strongest known risk factor. In the past, prophylactic oophorectomy has been advocated for women with two or more affected first-degree relatives. More recently, with the identification of the genes responsible for most hereditary ovarian cancers (BRCA1, BRCA2), oophorectomy can now be offered specifically to women who are mutation carriers. Conversely, noncarriers in these families can be reassured that their risk of ovarian cancer is not increased. The value of oophorectomy in mutation carriers has not yet been proven, however, and concern exists that the benefit may be less than intuitively expected. First, although the lifetime risk of ovarian cancer initially was reported to be as high as 60%, more recent studies have suggested risks in the range of 15 to 30%. A better understanding of the factors that underlie variable penetrance in mutation carriers is needed to augment our ability to counsel individual women. In addition, peritoneal papillary serous carcinoma indistinguishable from ovarian cancer occurs in some women after oophorectomy. Studies that better define the frequency with which this occurs are needed to establish the magnitude of the protective effect conferred by prophylactic oophorectomy. In view of the uncertainty regarding the efficacy of prophylactic oophorectomy, chemopreventive and early detection approaches also deserve consideration as strategies for decreasing ovarian cancer mortality in women who carry mutations in ovarian cancer susceptibility genes.

Authors
Berchuck, A; Schildkraut, JM; Marks, JR; Futreal, PA
MLA Citation
Berchuck, A, Schildkraut, JM, Marks, JR, and Futreal, PA. "Managing hereditary ovarian cancer risk." Cancer 86.11 Suppl (December 1, 1999): 2517-2524. (Review)
PMID
10630177
Source
pubmed
Published In
Cancer
Volume
86
Issue
11 Suppl
Publish Date
1999
Start Page
2517
End Page
2524

Isolation and initial characterization of the BRCA2 promoter.

The hereditary breast cancer susceptibility gene, BRCA2, is considered to be a tumor suppressor gene that may be involved in the cellular response to DNA damage. The transcript for this gene is cell cycle regulated with mRNA levels reaching a peak just before the onset of DNA synthesis. In order to define the mechanisms by which BRCA2 is transcriptionally regulated, we have begun to study upstream regulatory sequences. In this report, we define a minimal promoter region that has strong activity in human breast epithelial cells. Deletions of this sequence narrowed the strong basal activity to a region extending from -66 to +129 with respect to the BRCA2 transcriptional start site. This sequence demonstrated cell cycle regulated activity with kinetics similar to the endogenous transcript. Examination of the sequence revealed several consensus binding sites for transcription factors including an E-box, E2F and Ets recognition motifs. Electrohoretic mobility shift assays revealed specific protein binding to two sequences upstream of the start site; the palindromic E-box and an Ets/E2F site. Site-directed mutagenesis of either of these sites reduced both the basal activity in log phase cells and the cell cycle regulated activity of the promoter. Mutational inactivation of both sites within the same construct effectively eliminated promoter activity. Antibodies to candidate transcription factors used in super shift experiments revealed specific interactions between the BRCA2 promoter and the basic region/helix - loop - helix containing USF-1 and 2 proteins and Elf-1, an Ets domain protein. Binding of these factors depended upon the presence of intact recognition sequences. The USF factors were shown to bind predominantly as a heterodimeric complex of USF-1 and 2 while Elf-1 bound the promoter when it was not occupied by USF. Co-transfection studies with USF proteins and the varicella zoster IE62 protein provide evidence for the involvement of endogenous and exogenous USF in the activation of the BRCA2 promoter. We propose that interactions between USF-1, USF-2 and Elf-1 play an important role in the transcriptional regulation of the BRCA2 gene.

Authors
Davis, PL; Miron, A; Andersen, LM; Iglehart, JD; Marks, JR
MLA Citation
Davis, PL, Miron, A, Andersen, LM, Iglehart, JD, and Marks, JR. "Isolation and initial characterization of the BRCA2 promoter." Oncogene 18.44 (October 28, 1999): 6000-6012.
PMID
10557089
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
18
Issue
44
Publish Date
1999
Start Page
6000
End Page
6012
DOI
10.1038/sj.onc.1202990

Managing hereditary ovarian cancer risk

Authors
Berchuck, A; Schildkraut, JM; Marks, JR; Futreal, PA
MLA Citation
Berchuck, A, Schildkraut, JM, Marks, JR, and Futreal, PA. "Managing hereditary ovarian cancer risk." October 15, 1999.
Source
wos-lite
Published In
Cancer
Volume
86
Issue
8
Publish Date
1999
Start Page
1697
End Page
1704
DOI
10.1002/(SICI)1097-0142(19991015)86:8+<1697::AID-CNCR8>3.0.CO;2-W

Bcl10 is not a target for frequent mutation in human carcinomas.

The recently described Bcl10 gene has been suggested to be a major target gene for inactivation in a variety of human cancers. In order to further evaluate the role of this gene in human adult malignancies, we have analysed a series of carcinomas for mutations in the Bcl10 gene. We have screened a panel of 174 carcinoma samples in total, comprised of 47 breast, 36 epithelial ovarian, 36 endometrial, 12 cervical, 23 colorectal and 20 head/neck carcinomas, all unselected for grade or stage. This panel reflects, in part, tumours reported to have involvement of the 1p22 region of chromosome 1, the region harbouring the Bcl10 gene. No deleterious mutations were detected in any of the samples analysed, strongly suggesting that Bcl10 is not a common target for inactivation in adult malignancies and that BCL10 is not the gene targeted for frequent inactivation at 1p22.

Authors
Lambers, AR; Gumbs, C; Ali, S; Marks, JR; Iglehart, JD; Berchuck, A; Futreal, PA
MLA Citation
Lambers, AR, Gumbs, C, Ali, S, Marks, JR, Iglehart, JD, Berchuck, A, and Futreal, PA. "Bcl10 is not a target for frequent mutation in human carcinomas." Br J Cancer 80.10 (July 1999): 1575-1576.
PMID
10408401
Source
pubmed
Published In
British Journal of Cancer
Volume
80
Issue
10
Publish Date
1999
Start Page
1575
End Page
1576
DOI
10.1038/sj.bjc.6690564

Co-expression of p53 by epithelial and stromal elements in carcinosarcoma of the female genital tract: an immunohistochemical study of 19 cases.

Carcinosarcoma is an aggressive neoplasm of the female genital tract, which comprises 1-2% of malignancies of the uterine corpus. Because of the broad range of differentiation exhibited by these tumors, the precise nature of the relationship between epithelial and stromal components in this unique tumor remain unclear. Previous studies have demonstrated that mutation and consequent overexpression of the tumor suppressor gene p53 occurs frequently in carcinosarcoma and is conserved from primary to metastastic sites. We examined p53 accumulation in formalin-fixed, paraffin-embedded archival sections in 19 cases previously shown to have mutations in the p53 gene and performed semi-quantitative analysis of the intensity of staining and relative density of positive cells and stromal and glandular elements. There was a high level of concordance of immunohistochemical staining for the p53 oncoprotein between glandular and stromal elements. These results further suggest a clonal origin for the diverse elements of carcinosarcoma.

Authors
Szukala, SA; Marks, JR; Burchette, JL; Elbendary, AA; Krigman, HR
MLA Citation
Szukala, SA, Marks, JR, Burchette, JL, Elbendary, AA, and Krigman, HR. "Co-expression of p53 by epithelial and stromal elements in carcinosarcoma of the female genital tract: an immunohistochemical study of 19 cases." Int J Gynecol Cancer 9.2 (March 1999): 131-136.
PMID
11240754
Source
pubmed
Published In
International Journal of Gynecological Cancer
Volume
9
Issue
2
Publish Date
1999
Start Page
131
End Page
136

Multiple DNA repair mechanisms and alkylator resistance in the human medulloblastoma cell line D-283 Med (4-HCR).

PURPOSE: We have previously reported preferential repair of DNA interstrand crosslinks in the 4-hydroperoxycyclophosphamide-resistant human medulloblastoma cell line D-283 Med (4-HCR). We now report further studies that explored the potential mechanisms underlying this repair. METHODS: Limiting dilution assays and Western, Southern, and Northern blots were used to compare specific differences between D-283 Med (4-HCR) and its parental line D-283 Med. RESULTS: D-283 Med (4-HCR) was cross-resistant to melphalan and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), with O6-alkylguanine-DNA alkyltransferase (AGT) levels of 466+/-164 fmol/mg protein; AGT levels in the parental line, D-283 Med, were 76+/-96 fmol/mg. The increase in AGT activity was not a result of gene amplification. Depleting AGT with O6-benzylguanine partially restored sensitivity to BCNU. Both cell lines were deficient in the human mismatch protein MutLalpha. ERCC4 mRNA and poly(ADP-ribose) polymerase levels were similar in both cell lines, and ERCC1 mRNA levels were 2- to 2.5-fold lower in D-283 Med (4-HCR). Topoisomerase I levels were 2- to 2.5-fold higher in D-283 Med compared with D-283 Med (4-HCR). CONCLUSION: These results, while illustrating the multiple differences between D-283 Med and D-283 Med (4-HCR), do not explain the enhanced DNA interstrand crosslink repair seen in D-283 Med (4-HCR).

Authors
Dong, Q; Johnson, SP; Colvin, OM; Bullock, N; Kilborn, C; Runyon, G; Sullivan, DM; Easton, J; Bigner, DD; Nahta, R; Marks, J; Modrich, P; Friedman, HS
MLA Citation
Dong, Q, Johnson, SP, Colvin, OM, Bullock, N, Kilborn, C, Runyon, G, Sullivan, DM, Easton, J, Bigner, DD, Nahta, R, Marks, J, Modrich, P, and Friedman, HS. "Multiple DNA repair mechanisms and alkylator resistance in the human medulloblastoma cell line D-283 Med (4-HCR)." Cancer Chemother Pharmacol 43.1 (1999): 73-79.
PMID
9923544
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
43
Issue
1
Publish Date
1999
Start Page
73
End Page
79
DOI
10.1007/s002800050865

Telomerase activity and prognosis in primary breast cancers

Purpose: Recent studies associate telomerase activity with prognostic factors and survival. We compared quantitative telomerase activity in primary tumors with traditional prognostic factors and outcome in a group of invasive but nonmetastatic breast cancers. Patients and Methods: Telomerase activity was measured in 203 invasive breast cancers by the quantitative telomeric repeat amplification protocol method. Telomerase expression was compared with 28S rRNA level, tumor content, and clinical variables, including outcome. For clinical correlations, telomerase activity was standardized by two methods: (1) a correction for cellularity using 28S rRNA levels, and (2) a correction for the histologically determined invasive proportion of the specimen. Results: Telomerase activity was found in 82% of breast cancers with measurable 28S rRNA levels. Telomerase activity was associated with the proliferative index (P < .01) of the tumor but not with any other prognostic variable. Neither uncorrected nor corrected telomerase activity was associated with relapse-free or overall survival in this study. Conclusion: Telomerase activity level was associated with the proliferative index of invasive breast cancers, but its measurement in samples from this group of nonmetastatic breast cancer patients did not predict survival.

Authors
Carey, LA; Kim, NW; Goodman, S; Marks, J; Henderson, G; Umbricht, CB; Dome, JS; Dooley, W; Amshey, SR; Sukumar, S
MLA Citation
Carey, LA, Kim, NW, Goodman, S, Marks, J, Henderson, G, Umbricht, CB, Dome, JS, Dooley, W, Amshey, SR, and Sukumar, S. "Telomerase activity and prognosis in primary breast cancers." Journal of Clinical Oncology 17.10 (1999): 3075-3081.
PMID
10506602
Source
scival
Published In
Journal of Clinical Oncology
Volume
17
Issue
10
Publish Date
1999
Start Page
3075
End Page
3081

Telomerase activity in ductal carcinoma in situ and invasive breast cancer

The increasing number of breast carcinoma in situ detected by screening procedures makes it imperative to develop improved markers to stratify the risk of invasive cancer. Telomerase is detectable in invasive cancer, but not in normal tissues. We have microdissected frozen tissue blocks containing both DCIS and invasive cancer to assay the telomerase activity of these two lesions. The 46 available cases of concurrent DCIS and invasive breast cancer resulted in 43 DCIS samples and 38 invasive cancer samples adequate for analysis. Seventy per cent of the DCIS and all invasive cancer samples tested had detectable telomerase activity. In addition, we analysed telomerase activity in ten cases of DCIS that were not associated with invasive cancer, and detected telomerase activity in seven (70%). Mixing experiments showed no evidence of telomerase inhibitors in telomerase negative samples. Furthermore, periductal inflammatory infiltrates were shown to be a potential confounding source of telomerase activity. Since DCIS lesions appear to be heterogeneous with respect to telomerase activity, and telomerase activation appears to precede the development of invasive cancer, telomerase activity may be a useful adjunct in stratifying the risk of developing invasive breast cancer in patients with DCIS.

Authors
Umbricht, CB; Sherman, ME; Dome, J; Carey, LA; Marks, J; Kim, N; Sukumar, S
MLA Citation
Umbricht, CB, Sherman, ME, Dome, J, Carey, LA, Marks, J, Kim, N, and Sukumar, S. "Telomerase activity in ductal carcinoma in situ and invasive breast cancer." Oncogene 18.22 (1999): 3407-3414.
PMID
10362362
Source
scival
Published In
Oncogene: Including Oncogene Reviews
Volume
18
Issue
22
Publish Date
1999
Start Page
3407
End Page
3414
DOI
10.1038/sj.onc.1202714

Managing hereditary ovarian cancer risk

Ovarian cancer is the fourth leading cause of cancer deaths in American women About 10% of cases are thought to have a hereditary basis, and family history is the strongest known risk factor. In the past, prophylactic oophorectomy has been advocated for women with two or more affected first- degree relatives. More recently, with the identification of the genes responsible for most hereditary ovarian cancers (BRCA1, BRCA2), oophorectomy can now be offered specifically to women who are mutation carriers. Conversely, noncarriers in these families can be reassured that their risk of ovarian cancer is not increased. The value of oophorectomy in mutation carriers has not yet been proven, however, and concern exists that the benefit may be less than intuitively expected. First, although the lifetime risk of ovarian cancer initially was reported to be as high as 60%, more recent studies have suggested risks in the range of 15 to 30%. A better understanding of the factors that underlie variable penetrance in mutation carriers is needed to augment our ability to counsel individual women. In addition, peritoneal papillary serous carcinoma indistinguishable from ovarian cancer occurs in some women after oophorectomy. Studies that better define the frequency with which this occurs are needed to establish the magnitude of the protective effect conferred by prophylactic oophorectomy. In view of the uncertainty regarding the efficacy of prophylactic oophorectomy, chemopreventive and early detection approaches also deserve consideration as strategies for decreasing ovarian cancer mortality in women who carry mutations in ovarian cancer susceptibility genes.

Authors
Berchuck, A; Schildkraut, JM; Marks, JR; Futreal, PA
MLA Citation
Berchuck, A, Schildkraut, JM, Marks, JR, and Futreal, PA. "Managing hereditary ovarian cancer risk." Cancer 86.11 SUPPL. (1999): 2517-2524.
Source
scival
Published In
Cancer
Volume
86
Issue
11 SUPPL.
Publish Date
1999
Start Page
2517
End Page
2524

Relationship between alterations in the p53 gene and chemosensitivity of ovarian cancers

It is thought that the cytotoxic effect of chemotherapy drugs is largely due to their ability to initiate programmed cell death (apoptosis). Although the molecular pathways involved in regulation of apoptosis have not been completely elucidated, it has been shown that the p53 tumor suppressor gene plays a significant role in this process. Mutations in the p53 gene are a frequent event in ovarian cancers and it has been postulated that loss of functional p53 might confer resistance to chemotherapy drugs such as cisplatin, alkylating agents and paclitaxel. The data in the literature do not consistently support this hypothesis, however. Although some experimental studies have suggested mutant p53 is associated with a resistant phenotype, other studies have clearly demonstrated that chemosensitivity is not solely determined by the status of the p53 gene. The current body of evidence suggests that regulation of chemotherapy induced apoptosis involves a complex series of molecular events. As the intricacies of these pathways are unraveled, hopefully these insights will prove useful in predicting chemoresponsiveness of individual ovarian cancers.

Authors
Berchuck, A; Maxwell, GL; Marks, JR
MLA Citation
Berchuck, A, Maxwell, GL, and Marks, JR. "Relationship between alterations in the p53 gene and chemosensitivity of ovarian cancers." CME Journal of Gynecologic Oncology 4.1 (1999): 78-81.
Source
scival
Published In
CME Journal of Gynecologic Oncology
Volume
4
Issue
1
Publish Date
1999
Start Page
78
End Page
81

Repression of interleukin-2 mRNA translation in primary human breast carcinoma tumor-infiltrating lymphocytes.

Human breast carcinoma tumor-infiltrating lymphocytes (TIL) express activation antigens in situ indicative of ongoing immune response-CD28, CD45RO, CD69, CD71, and DR. However, interleukin 2 (IL-2) receptor was poorly expressed: CD25 was detected in only 1/24 samples and CD122 in only 2/24 samples. Furthermore, isolated breast cancer TIL were defective in proliferative response but recover when treated with recombinant IL-2. Nineteen of 24 tumor samples expressed B7-1, B7-2, and CD28 protein, showing that absence of costimulator proteins or counter ligand was not the basis for TIL proliferative deficit. Expression of IL-2 activity was not detected; however, mRNA encoding IL-2 was produced and translatable in vitro. These findings show that human breast cancer tumor-induced repression of IL-2 RNA translation is the basis of failure of TIL to express the IL-2 receptor and subsequent T cell hyporesponsiveness.

Authors
Lopez, CB; Rao, TD; Feiner, H; Shapiro, R; Marks, JR; Frey, AB
MLA Citation
Lopez, CB, Rao, TD, Feiner, H, Shapiro, R, Marks, JR, and Frey, AB. "Repression of interleukin-2 mRNA translation in primary human breast carcinoma tumor-infiltrating lymphocytes." Cell Immunol 190.2 (December 15, 1998): 141-155.
PMID
9878115
Source
pubmed
Published In
Cellular Immunology
Volume
190
Issue
2
Publish Date
1998
Start Page
141
End Page
155
DOI
10.1006/cimm.1998.1390

Frequency of germline and somatic BRCA1 mutations in ovarian cancer.

Germline mutations in the BRCA1 tumor suppressor gene are thought to be the most common cause of hereditary ovarian cancer. The aim of this study was to explore further the role of BRCA1 alterations in the development of ovarian cancers. We sought to determine whether somatic BRCA1 mutations are ever present in ovarian cancers and whether mutation is always accompanied by loss of the wild-type allele. The entire coding region and intronic splice sites of BRCA1 were sequenced using genomic DNA samples from 103 unselected ovarian cancers. Thirteen clearly deleterious BRCA1 mutations and two variants of uncertain significance were found. Blood DNA was available in all but two cases and demonstrated that 4 of 13 mutations and both variants of uncertain significance were germline alterations, whereas in seven cases the mutation was a somatic change present only in the cancer. Using four microsatellite markers, loss of heterozygosity at the BRCA1 locus was found in all 15 ovarian cancers with BRCA1 sequence alterations, compared with only 58% of ovarian cancers that did not have BRCA1 mutations. BRCA1-associated ovarian cancers were characterized by serous histology and moderate histological grade. These data confirm prior reports suggesting that germline mutations in BRCA1 are present in about 5% of women with ovarian cancer. In addition, somatic mutations in BRCA1 occur in the development of some sporadic cases. The finding that both germline and somatic BRCA1 mutations are accompanied by loss of heterozygosity, suggests that loss of this tumor suppressor gene is a critical event in the development of these cancers.

Authors
Berchuck, A; Heron, KA; Carney, ME; Lancaster, JM; Fraser, EG; Vinson, VL; Deffenbaugh, AM; Miron, A; Marks, JR; Futreal, PA; Frank, TS
MLA Citation
Berchuck, A, Heron, KA, Carney, ME, Lancaster, JM, Fraser, EG, Vinson, VL, Deffenbaugh, AM, Miron, A, Marks, JR, Futreal, PA, and Frank, TS. "Frequency of germline and somatic BRCA1 mutations in ovarian cancer." Clin Cancer Res 4.10 (October 1998): 2433-2437.
PMID
9796975
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
4
Issue
10
Publish Date
1998
Start Page
2433
End Page
2437

Aberrant splicing of the TSG101 tumor suppressor gene in human breast and ovarian cancers.

OBJECTIVE: To determine whether large deletions or other alterations in the putative tumor suppressor gene TSG101 play a role in the molecular pathogenesis of breast and ovarian cancers. METHODS: Expression of TSG101 transcripts was examined in breast and ovarian cancers using the reverse transcriptase-polymerase chain reaction (RT-PCR), and selected transcripts were sequenced. Southern blot analysis was performed to determine whether there were genomic deletions in the TSG101 gene, and Northern blot analysis was used to examine the relative abundance of various transcripts. RESULTS: All the cancerous and normal breast tissue examined expressed full length 1145 base pair (bp) TSG101 transcripts. Additional truncated transcripts were seen using the RT-PCR in 57 (64%) of 89 primary breast cancers, 1 (20%) of 5 breast cancer cell lines, 3 (50%) of 6 normal breast tissues, 16 (64%) of 25 primary ovarian cancers and 1 (33%) of 3 ovarian cancer cell lines. Only the primary breast (21%) and ovarian (24%) cancers had three or more truncated transcripts. None of the normal tissues or cell lines examined had more than two aberrant transcripts. DNA sequencing revealed that the most commonly expressed truncated transcript arises because of loss of 902 bp between codons 153 and 1055. Only full length TSG101 transcripts were seen on Northern blot analysis of breast cancer cell lines, however. There was no evidence of genomic deletions in the TSG101 gene on Southern blot analysis. CONCLUSION: Truncated TSG101 transcripts that probably represent splice variants are present in some breast and ovarian cancers, but there is no evidence to suggest that loss of this putative tumor suppressor gene plays a role in the molecular pathogenesis of these cancers.

Authors
Carney, ME; Maxwell, GL; Lancaster, JM; Gumbs, C; Marks, J; Berchuck, A; Futreal, PA
MLA Citation
Carney, ME, Maxwell, GL, Lancaster, JM, Gumbs, C, Marks, J, Berchuck, A, and Futreal, PA. "Aberrant splicing of the TSG101 tumor suppressor gene in human breast and ovarian cancers." J Soc Gynecol Investig 5.5 (September 1998): 281-285.
PMID
9773405
Source
pubmed
Published In
Journal of the Society for Gynecologic Investigation (Elsevier)
Volume
5
Issue
5
Publish Date
1998
Start Page
281
End Page
285

Complex response of breast epithelial cell lines to topoisomerase inhibitors.

The topoisomerase inhibitors, camptothecin and etoposide target the activity of topoisomerase I and II respectively. These agents, or their analogues, are undergoing clinical trials for the treatment of metastatic breast cancer. In this study, we examined the response of eight breast epithelial cell lines, including six lines derived from breast cancers and two immortalized normal epithelial lines to camptothecin and etoposide. The lines varied by 700 fold in their sensitivity to the growth inhibiting effects of camptothecin and 30 fold in their response to etoposide. The BT474 line was the most resistant to both agents. The other cell lines did not have uniform sensitivity to both drugs, i.e., some lines were sensitive to one drug but relatively resistant to the other. A variety of parameters in these lines were analyzed to elucidate mechanisms of resistance including S phase, doubling time, expression and activity of topoisomerase I and II, expression of mdr-1, p53 status, cell cycle arrest, level of apoptosis, and expression of the apoptotic proteins Bcl-2 and Bax. We found that low levels of the topo I protein and its enzymatic activity were associated with increased resistance to camptothecin. This was not true for topo II activity and etoposide. Increased apoptotic responses were generally observed in cell lines that were sensitive to etoposide and this correlated with low ratios of Bcl-2/Bax protein. No single parameter was entirely predictive of response. However, the BT474 line displayed a series of characteristics including slow growth, the presence of mutant p53, low topo I activity, and a high Bcl-2/Bax ratio which together likely contributed to the resistance of this line to both etoposide and camptothecin.

Authors
Davis, PL; Shaiu, WL; Scott, GL; Iglehart, JD; Hsieh, TS; Marks, JR
MLA Citation
Davis, PL, Shaiu, WL, Scott, GL, Iglehart, JD, Hsieh, TS, and Marks, JR. "Complex response of breast epithelial cell lines to topoisomerase inhibitors." Anticancer Res 18.4C (July 1998): 2919-2932.
PMID
9713486
Source
pubmed
Published In
Anticancer research
Volume
18
Issue
4C
Publish Date
1998
Start Page
2919
End Page
2932

Predicting response to adjuvant and radiation therapy in patients with early stage breast carcinoma.

BACKGROUND: Screening and surveillance is increasing the detection of early stage breast carcinoma. The ability to predict accurately the response to adjuvant therapy (chemotherapy or tamoxifen therapy) or postlumpectomy radiation therapy in these patients can be vital to their survival, because this prediction determines the best postsurgical therapy for each patient. METHODS: This study evaluated data from 226 patients with TNM Stage I and early Stage II breast carcinoma and included the variables p53 and c-erbB-2 (HER-2/neu). The area under the receiver operating characteristic curve (Az) was the measure of predictive accuracy. The prediction endpoints were 5- and 10-year overall survival. RESULTS: For Stage I and early Stage II patients, the 5- and 10-year predictive accuracy of the TNM staging system were at chance level, i.e., no better than flipping a coin. Both the 5- and 10-year artificial neural networks (ANNs) were very accurate--significantly more so than the TNM staging system (Az 5-year survival, TNM = 0.567, ANN = 0.758; P < 0.001; Az 10-year survival, TNM = 0.508, ANN = 0.894; P < 0.0001). For patients not receiving postsurgical therapy and for either chemotherapy or tamoxifen therapy, the ANNs containing p53 and c-erbB-2 and the number of positive lymph nodes were accurate predictors of survival (Az 5-year survival, 0.781, 0.789, and 0.720, respectively). CONCLUSIONS: The molecular genetic variables p53 and c-erbB-2 and the number of positive lymph nodes are powerful predictors of survival, and using ANN statistical models is a powerful method for predicting responses to adjuvant therapy or radiation therapy in patients with breast carcinoma. ANNs with molecular genetic prognostic factors may improve therapy selection for women with early stage breast carcinoma.

Authors
Burke, HB; Hoang, A; Iglehart, JD; Marks, JR
MLA Citation
Burke, HB, Hoang, A, Iglehart, JD, and Marks, JR. "Predicting response to adjuvant and radiation therapy in patients with early stage breast carcinoma." Cancer 82.5 (March 1, 1998): 874-877.
PMID
9486576
Source
pubmed
Published In
Cancer
Volume
82
Issue
5
Publish Date
1998
Start Page
874
End Page
877

Familial breast-ovarian cancer syndromes: BRCA1 and BRCA2.

Authors
Berchuck, A; Carney, M; Lancaster, JM; Marks, J; Futreal, AP
MLA Citation
Berchuck, A, Carney, M, Lancaster, JM, Marks, J, and Futreal, AP. "Familial breast-ovarian cancer syndromes: BRCA1 and BRCA2." Clin Obstet Gynecol 41.1 (March 1998): 157-166. (Review)
PMID
9504233
Source
pubmed
Published In
Clinical Obstetrics and Gynecology
Volume
41
Issue
1
Publish Date
1998
Start Page
157
End Page
166

Expression of Tie2/Tek in breast tumour vasculature provides a new marker for evaluation of tumour angiogenesis.

Endothelial receptor tyrosine kinases may play important roles in pathological vascular growth, particularly in tumours. In this study, immunohistochemistry was used to evaluate the expression of a novel endothelial receptor tyrosine kinase, Tie2/Tek, in the endothelium of vascular 'hotspots' in normal breast tissue (n = 10), benign breast lesions (n = 10) and in breast tumours (n = 123). Tie2 expression was detected in the endothelium of all breast tissues examined. However, the strongest expression of Tie-2 was seen in vascular 'hot spots' within the inflammatory infiltrate at the periphery of invasive tumours. Moreover, the proportion of Tie2-positive vessels (Tie2 counts/CD31 counts) was significantly higher in breast tumours than the proportion of Tie2-positive vessels in either normal breast tissue or benign breast lesions (P = 0.004 and 0.0001 respectively). These data are consistent with a role for Tie2 in tumour angiogenesis and demonstrate the potential use of Tie2 expression as a novel marker of the tumour vasculature.

Authors
Peters, KG; Coogan, A; Berry, D; Marks, J; Iglehart, JD; Kontos, CD; Rao, P; Sankar, S; Trogan, E
MLA Citation
Peters, KG, Coogan, A, Berry, D, Marks, J, Iglehart, JD, Kontos, CD, Rao, P, Sankar, S, and Trogan, E. "Expression of Tie2/Tek in breast tumour vasculature provides a new marker for evaluation of tumour angiogenesis." Br J Cancer 77.1 (1998): 51-56.
PMID
9459145
Source
pubmed
Published In
British Journal of Cancer
Volume
77
Issue
1
Publish Date
1998
Start Page
51
End Page
56

Repression of IL-2 mRNA translation in primary human breast cancer tumor infiltrating lymphocytes

Tumor infiltrating lymphocytes (TIL) are abundant in primary human carcinomas but display diminished proliferative response to TCR ligation in vitro. We demonstrate by immunocytochemistry analysis that breast carcinoma TII. express both early and late cell surface activation antigens indicative of ongoing immune response. However, TIL were deficient in IL-2 receptor expression: CD25 was detected in only 1 out of 24 samples and CD122 was detected in only 2 samples. The common gamma subunit (CD132) was expressed in 21/24 tumors. RT-PCR analysis of tumor RNA showed moderate levels of CD122 mRNA in 5 out of 19 samples, 9 samples expressed no mRNA, and 5 samples expressed only very low (but detectable) mRNA. Similarly, moderate levels of CD25 RNA was detected in 1 tumor, very low levels were found in 4 tumors, and 14 tumors expressed no RNA. Furthermore, isolated breast cancer TILs were defective both in proliferative response and IL-2 receptor mRNA expression but recover when incubated in the presence of recombinant IL-2. 19/24 tumor samples expressed B7-1, B7-2, CD28, and CTLA-4 protein showing that absence of co-stimulator proteins or counter ligands was not the basis for TIL proliferative deficit. By bioassay of tumor explants IL-2 was not detected although mRNA encoding IL-2 was produced and was able to be translated in vitro. These findings show that human breast cancer TIL are anergic and suggest that tumor-induced repression of IL-2 RNA translation is the basis of failure to express the IL-2 receptor and subsequent T cell hyporesponsiveness.

Authors
Frey, AB; Lopez, C; Feiner, H; Shapiro, R; Marks, J; Rao, TD
MLA Citation
Frey, AB, Lopez, C, Feiner, H, Shapiro, R, Marks, J, and Rao, TD. "Repression of IL-2 mRNA translation in primary human breast cancer tumor infiltrating lymphocytes." 1998.
Source
scival
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
12
Issue
5
Publish Date
1998
Start Page
A889

Artificial neural networks improve the accuracy of cancer survival prediction.

BACKGROUND: The TNM staging system originated as a response to the need for an accurate, consistent, universal cancer outcome prediction system. Since the TNM staging system was introduced in the 1950s, new prognostic factors have been identified and new methods for integrating prognostic factors have been developed. This study compares the prediction accuracy of the TNM staging system with that of artificial neural network statistical models. METHODS: For 5-year survival of patients with breast or colorectal carcinoma, the authors compared the TNM staging system's predictive accuracy with that of artificial neural networks (ANN). The area under the receiver operating characteristic curve, as applied to an independent validation data set, was the measure of accuracy. RESULTS: For the American College of Surgeons' Patient Care Evaluation (PCE) data set, using only the TNM variables (tumor size, number of positive regional lymph nodes, and distant metastasis), the artificial neural network's predictions of the 5-year survival of patients with breast carcinoma were significantly more accurate than those of the TNM staging system (TNM, 0.720; ANN, 0.770; P < 0.001). For the National Cancer Institute's Surveillance, Epidemiology, and End Results breast carcinoma data set, using only the TNM variables, the artificial neural network's predictions of 10-year survival were significantly more accurate than those of the TNM staging system (TNM, 0.692; ANN, 0.730; P < 0.01). For the PCE colorectal data set, using only the TNM variables, the artificial neural network's predictions of the 5-year survival of patients with colorectal carcinoma were significantly more accurate than those of the TNM staging system (TNM, 0.737; ANN, 0.815; P < 0.001). Adding commonly collected demographic and anatomic variables to the TNM variables further increased the accuracy of the artificial neural network's predictions of breast carcinoma survival (0.784) and colorectal carcinoma survival (0.869). CONCLUSIONS: Artificial neural networks are significantly more accurate than the TNM staging system when both use the TNM prognostic factors alone. New prognostic factors can be added to artificial neural networks to increase prognostic accuracy further. These results are robust across different data sets and cancer sites.

Authors
Burke, HB; Goodman, PH; Rosen, DB; Henson, DE; Weinstein, JN; Harrell, FE; Marks, JR; Winchester, DP; Bostwick, DG
MLA Citation
Burke, HB, Goodman, PH, Rosen, DB, Henson, DE, Weinstein, JN, Harrell, FE, Marks, JR, Winchester, DP, and Bostwick, DG. "Artificial neural networks improve the accuracy of cancer survival prediction." Cancer 79.4 (February 15, 1997): 857-862.
PMID
9024725
Source
pubmed
Published In
Cancer
Volume
79
Issue
4
Publish Date
1997
Start Page
857
End Page
862

BRCA1 expression is not directly responsive to estrogen.

Expression of the breast cancer susceptibility gene, BRCA1, is induced by 17-beta estradiol (E2) in estrogen receptor containing breast cancer cell lines. Our previous studies have shown that BRCA1 transcription is also regulated with the cell cycle, reaching maximal levels just before the onset of DNA synthesis. In this study, we have examined whether the estrogen induction of BRCA1 is direct or is a result of the mitogenic activity of the hormone. Four lines of evidence lead us to conclude that E2 induces BRCA1 primarily through an increase in DNA synthesis: (1) The kinetics and magnitude of induction are different from the directly E2 inducible gene, pS2; (2) Induction of BRCA1, but not pS2, is blocked by cycloheximide indicating that de novo protein synthesis is required; (3) Other hormonal and growth factor treatments that induce DNA synthesis have a similar effect, including IGF-1, EGF and DNA synthetic flares induced by tamoxifen and retinoic acid; (4) BRCA1 genomic fragments near the 5' end of the gene containing putative estrogen response elements fail to respond to E2 when transfected into breast cancer cell lines. The most consistent explanation for these findings and other published studies is that BRCA1 transcription is induced as a result of the mitogenic activity of E2 in estrogen receptor positive cells.

Authors
Marks, JR; Huper, G; Vaughn, JP; Davis, PL; Norris, J; McDonnell, DP; Wiseman, RW; Futreal, PA; Iglehart, JD
MLA Citation
Marks, JR, Huper, G, Vaughn, JP, Davis, PL, Norris, J, McDonnell, DP, Wiseman, RW, Futreal, PA, and Iglehart, JD. "BRCA1 expression is not directly responsive to estrogen." Oncogene 14.1 (January 9, 1997): 115-121.
PMID
9010238
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
14
Issue
1
Publish Date
1997
Start Page
115
End Page
121
DOI
10.1038/sj.onc.1200808

Inhibition of the erbB-2 tyrosine kinase receptor in breast cancer cells by phosphoromonothioate and phosphorodithioate antisense oligonucleotides.

Antisense activity against erbB-2 of a variety of sulfur-modified oligonucleotides was examined in a breast cancer cell line which overexpresses this oncogene. Using a 15 base anti-erbB-2 sequence previously shown to be effective, various backbone configurations containing phosphoromonothioate or phosphorodithioate linkages were evaluated for antisense activity by a two-color flow cytometric assay. This sequence was effective in inhibiting the production of erbB-2 protein when it was configured as a monothioate at each linkage and as an alternating dithioate/phosphodiester. Both of these compounds were also able to specifically inhibit erbB-2 mRNA expression, indicative of RNase H-mediated activity. The same sequence protected by either three dithioate or three monothioate linkages at each end was ineffective as an antisense reagent, suggesting that endonuclease activity is a significant determinant of the stability of oligonucleotides. Finally, the erbB-2 sequence target was shifted in an effort to improve antisense activity. A new lead sequence was identified that was significantly more effective in inhibiting erbB-2 protein levels and retained activity at lower concentrations.

Authors
Vaughn, JP; Stekler, J; Demirdji, S; Mills, JK; Caruthers, MH; Iglehart, JD; Marks, JR
MLA Citation
Vaughn, JP, Stekler, J, Demirdji, S, Mills, JK, Caruthers, MH, Iglehart, JD, and Marks, JR. "Inhibition of the erbB-2 tyrosine kinase receptor in breast cancer cells by phosphoromonothioate and phosphorodithioate antisense oligonucleotides." Nucleic Acids Res 24.22 (November 15, 1996): 4558-4564.
PMID
8948649
Source
pubmed
Published In
Nucleic Acids Research
Volume
24
Issue
22
Publish Date
1996
Start Page
4558
End Page
4564

Tissue transglutaminase expression in human breast cancer.

Tissue transglutaminase (tTG) is postulated to play a role in apoptosis, cell adhesion, metastasis, and extracellular matrix (ECM) assembly. In this study, the distribution and expression of tissue transglutaminase was investigated in normal human mammary tissue and in intraductal and invasive human breast cancer by immunohistochemistry and in situ hybridization. Frozen and formalin-fixed paraffin-embedded sections of normal, intraductal, and invasive human breast carcinoma were examined with an avidin-biotin complex immunoperoxidase method for tTG antigen and by in situ hybridization to determine the cell types expressing tTG mRNA. The expression of tTG in normal and malignant mammary epithelium in culture was evaluated by quantitative immunoblot analysis. Low-level expression of tTG was found in normal tissues with the antigen located in the ECM surrounding the ducts and in the endothelium. In intraductal cancer, there was a marked increased expression of the tTG antigen, and the increased staining was found in the ECM and was also localized in a distinct pattern at the boundary between the in situ tumor cells and the normal tissue. Further immunohistochemical analysis revealed that the cells in this boundary also stained for the endothelial cell markers CD31, CD34, and von Willebrand factor. In invasive tumors, the tTG antigen was no longer localized to the normal tissue/tumor boundary but dispersed around the tumor cells. In situ hybridization studies revealed three distinct compartments of tTG synthesis: (a) tumor cells, (b) endothelial cells, and (c) stromal cells. In addition, normal and malignant epithelial cells in culture expressed variable amounts of tTG, and the expression of tTG in these epithelial cells was at least 17-fold less than endothelial cells. The up-regulation of tTG in intraductal and invasive human breast cancer and its localization to the ECM and neovasculature suggest that tTG may regulate tumor growth and metastasis.

Authors
Hettasch, JM; Bandarenko, N; Burchette, JL; Lai, TS; Marks, JR; Haroon, ZA; Peters, K; Dewhirst, MW; Iglehart, JD; Greenberg, CS
MLA Citation
Hettasch, JM, Bandarenko, N, Burchette, JL, Lai, TS, Marks, JR, Haroon, ZA, Peters, K, Dewhirst, MW, Iglehart, JD, and Greenberg, CS. "Tissue transglutaminase expression in human breast cancer." Lab Invest 75.5 (November 1996): 637-645.
PMID
8941210
Source
pubmed
Published In
Laboratory Investigation
Volume
75
Issue
5
Publish Date
1996
Start Page
637
End Page
645

Microsomal epoxide hydrolase polymorphism as a risk factor for ovarian cancer.

Microsomal epoxide hydrolase (EPHX) is one of many enzymes involved in the metabolism of endogenous and exogenous toxicants. Polymorphic forms of the human EPHX gene have been described that vary in enzymatic activity, and one, Tyr113His, has been associated with hepatocellular carcinoma susceptibility. We demonstrated that EPHX was highly expressed in the human ovary, and investigated whether specific EPHX genotypes are associated with ovarian cancer susceptibility. Seventy-three Caucasian patients with ovarian cancer and 75 Caucasian-female controls without cancer were genotyped for the Tyr113His polymorphism by a polymerase chain reaction-restriction fragment length polymorphism assay. The frequency of the homozygous high-activity genotype was 41% in the control population and 64% in the ovarian cancer patients. The odds ratio for ovarian cancer with this genotype was 2.6 (95% confidence interval 1.3, 5.0; P < 0.01). The increased ovarian cancer risk associated with the high-activity genotype could reflect differences in metabolic activation of endogenous or exogenous carcinogens.

Authors
Lancaster, JM; Brownlee, HA; Bell, DA; Futreal, PA; Marks, JR; Berchuck, A; Wiseman, RW; Taylor, JA
MLA Citation
Lancaster, JM, Brownlee, HA, Bell, DA, Futreal, PA, Marks, JR, Berchuck, A, Wiseman, RW, and Taylor, JA. "Microsomal epoxide hydrolase polymorphism as a risk factor for ovarian cancer." Mol Carcinog 17.3 (November 1996): 160-162.
PMID
8944076
Source
pubmed
Published In
Molecular Carcinogenesis
Volume
17
Issue
3
Publish Date
1996
Start Page
160
End Page
162
DOI
10.1002/(SICI)1098-2744(199611)17:3<160::AID-MC8>3.0.CO;2-J

p53 overexpression in advanced-stage endometrial adenocarcinoma.

OBJECTIVES: Mutation and overexpression of the p53 tumor suppressor gene in endometrial cancers are associated with advanced stage and poor survival. We sought to determine whether p53 overexpression is an independent variable predictive of poor prognosis in advanced endometrial adenocarcinomas. STUDY DESIGN: Immunohistochemical evaluation was used to examine p53 expression in paraffin blocks from 179 endometrial adenocarcinomas. RESULTS: p53 overexpression was seen in 35% of cancers and was associated with higher stage (p = 0.004), black race (p < 0.001), higher grade (p = 0.02), lack of hormone replacement (p = 0.04), and older age (p = 0.05). In addition to a higher frequency of p53 overexpression (57% vs 26%), black women had a lower survival rate than white women (p = 0.001), but overexpression was associated with poor survival in both races. After we corrected for hormone use, multivariate analysis revealed that older age (p < 0.001), higher stage (p < 0.001), higher grade (p = 0.01), and p53 overexpression (p = 0.04) were predictive of poor survival. CONCLUSIONS: Overexpression of p53 in advanced-stage endometrial cancers is an independent variable that is associated with poor survival, occurs more frequently in black women, and may contribute to the racial disparity in survival.

Authors
Kohler, MF; Carney, P; Dodge, R; Soper, JT; Clarke-Pearson, DL; Marks, JR; Berchuck, A
MLA Citation
Kohler, MF, Carney, P, Dodge, R, Soper, JT, Clarke-Pearson, DL, Marks, JR, and Berchuck, A. "p53 overexpression in advanced-stage endometrial adenocarcinoma." Am J Obstet Gynecol 175.5 (November 1996): 1246-1252.
PMID
8942496
Source
pubmed
Published In
American Journal of Obstetrics & Gynecology
Volume
175
Issue
5
Publish Date
1996
Start Page
1246
End Page
1252

Cell cycle control of BRCA2.

Identifying the conditions and kinetics of the induction of BRCA2 gene expression may implicate roles for the function of the tumor suppressor gene. In this study, expression of BRCA2 mRNA is shown to be regulated by the cell cycle and associated with proliferation in normal and tumor-derived breast epithelial cells. Cells arrested in G(0) or early G1 contained low levels of BRCA2 mRNA. After release into a proliferating state, cells produced maximum levels of BRCA2 mRNA in late G1 and the S-phase. Similar cell cycle control of BRCA2 was observed in fractions of exponentially growing cells isolated by centrifugal elutriation. Expression of BRCA2 was shown to be independent of bulk DNA synthesis. In addition, the kinetics of BRCA2 mRNA up-regulation appeared to be similar to those of BRCA1, suggesting that the two genes could be commonly controlled. These results imply that these two tumor suppressor genes are utilized during growth and may have a protective role in cellular proliferation.

Authors
Vaughn, JP; Cirisano, FD; Huper, G; Berchuck, A; Futreal, PA; Marks, JR; Iglehart, JD
MLA Citation
Vaughn, JP, Cirisano, FD, Huper, G, Berchuck, A, Futreal, PA, Marks, JR, and Iglehart, JD. "Cell cycle control of BRCA2." Cancer Res 56.20 (October 15, 1996): 4590-4594.
PMID
8840967
Source
pubmed
Published In
Cancer Research
Volume
56
Issue
20
Publish Date
1996
Start Page
4590
End Page
4594

Relationship between p21 expression and mutation of the p53 tumor suppressor gene in normal and malignant ovarian epithelial cells.

In many cell types, p53-mediated growth inhibition is dependent on induction of p21, which is an inhibitor of cyclin-dependent kinases that are required for cell cycle progression. Failure of mutant p53 proteins to transactivate p21 may lead to uncontrolled proliferation. Because many ovarian cancers have mutations in the p53 gene, we examined p21 levels in normal and malignant ovarian epithelial cells to determine whether p21 expression is dependent on wild-type p53. Normal ovarian epithelial cells and two ovarian cancer cell lines with wild-type p53 expressed readily detectable levels of p21, whereas in p53 null and mutant cell lines, expression of p21 was diminished strikingly. A correlation between the status of the p53 gene and p21 expression also was noted in 23 primary epithelial ovarian cancers. Normal levels of p21 RNA were seen in 4/7 (57%) cancers with wild-type p53, whereas 14/16 (88%) cancers with mutant p53 had reduced p21 expression (P < 0.05). In addition, we found that lambda-irradiation of normal and malignant ovarian epithelial cells with wild-type, but not mutant, p53 resulted in induction of p21. These data are suggestive that induction of p21 is a feature of p53-mediated growth inhibition in normal ovarian epithelial cells. Conversely, mutation of the p53 gene in ovarian cancers usually is associated with decreased p21 expression. The lack of an absolute correlation between p21 expression and the status of the p53 gene in ovarian cancers is consistent with other studies that have suggested that p21 may also be regulated by p53-independent pathways.

Authors
Elbendary, AA; Cirisano, FD; Evans, AC; Davis, PL; Iglehart, JD; Marks, JR; Berchuck, A
MLA Citation
Elbendary, AA, Cirisano, FD, Evans, AC, Davis, PL, Iglehart, JD, Marks, JR, and Berchuck, A. "Relationship between p21 expression and mutation of the p53 tumor suppressor gene in normal and malignant ovarian epithelial cells." Clin Cancer Res 2.9 (September 1996): 1571-1575.
PMID
9816335
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
2
Issue
9
Publish Date
1996
Start Page
1571
End Page
1575

Role of BRCA1 mutation screening in the management of familial ovarian cancer.

Families with multiple cases of ovarian cancer have long been observed, and in the past prophylactic oophorectomy has been advocated for women with a history of ovarian cancer in two first-degree relatives. It is now thought that > 90% of familial ovarian cancer is due to inherited mutations in the BRCA1 breast-ovarian cancer susceptibility gene on chromosome 17q. BRCA1 testing is being performed in several academic medical centers on a research basis and is also now commercially available. With the ability to identify inherited mutations in BRCA1, prophylactic oophorectomy and other interventions intended to decrease cancer mortality can be offered specifically to women who carry a mutation, but the optimal strategy for decreasing cancer mortality in BRCA1 families has not yet been determined. To facilitate further clinical and basic research in this field, our group and others have established multidisciplinary hereditary breast-ovarian cancer clinics that offer a wide range of services including BRCA1 testing, genetic counseling, and cancer prevention and treatment.

Authors
Berchuck, A; Cirisano, F; Lancaster, JM; Schildkraut, JM; Wiseman, RW; Futreal, A; Marks, JR
MLA Citation
Berchuck, A, Cirisano, F, Lancaster, JM, Schildkraut, JM, Wiseman, RW, Futreal, A, and Marks, JR. "Role of BRCA1 mutation screening in the management of familial ovarian cancer." Am J Obstet Gynecol 175.3 Pt 1 (September 1996): 738-746. (Review)
PMID
8828444
Source
pubmed
Published In
American Journal of Obstetrics & Gynecology
Volume
175
Issue
3 Pt 1
Publish Date
1996
Start Page
738
End Page
746

BRCA1 expression is induced before DNA synthesis in both normal and tumor-derived breast cells.

Insight into the function of the BRCA1 tumor suppressor gene may be gained by studying its regulation. In this study, the expression of BRCA1 was examined as a function of the cell cycle in normal and tumor-derived breast epithelial cells. Cells arrested in G(zero) or early in G1 contained low levels of BRCA1 mRNA. After release, populations of cells reached maximal levels of BRCA1 in late G1 and S phase. Induction of BRCA1 was shown to occur before the onset of DNA synthesis by synchronizing cells at the G1-S boundary. Levels of the BRCA1 protein were regulated in a similar manner. No difference was observed between primary cultures of normal mammary epithelial cells and immortalized tumor-derived cell lines. These results suggest that BRCA1 may function at the G1-S checkpoint.

Authors
Vaughn, JP; Davis, PL; Jarboe, MD; Huper, G; Evans, AC; Wiseman, RW; Berchuck, A; Iglehart, JD; Futreal, PA; Marks, JR
MLA Citation
Vaughn, JP, Davis, PL, Jarboe, MD, Huper, G, Evans, AC, Wiseman, RW, Berchuck, A, Iglehart, JD, Futreal, PA, and Marks, JR. "BRCA1 expression is induced before DNA synthesis in both normal and tumor-derived breast cells." Cell Growth Differ 7.6 (June 1996): 711-715.
PMID
8780884
Source
pubmed
Published In
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research
Volume
7
Issue
6
Publish Date
1996
Start Page
711
End Page
715

BRCA2 mutations in primary breast and ovarian cancers.

The second hereditary breast cancer gene, BRCA2, was recently isolated. Germline mutations of this gene predispose carriers to breast cancer, and, to a lesser extent, ovarian cancer. Loss of heterozygosity (LOH) at the BRCA2 locus has been observed in 30-40% of sporadic breast and ovarian tumours, implying that BRCA2 may act as a tumour suppressor gene in a proportion of sporadic cases. To define the role of BRCA2 in sporadic breast and ovarian cancer, we screened the entire gene for mutations using a combination of techniques in 70 primary breast carcinomas and in 55 primary epithelial ovarian carcinomas. Our analysis revealed alterations in 2/70 breast tumours and none of the ovarian carcinomas. One alteration found in the breast cancers was a 2-basepair (bp) deletion (4710delAG) which was subsequently shown to be a germline mutation, the other was a somatic missense mutation (Asp3095Glu) of unknown significance. Our results suggest that BRCA2 is a very infrequent target for somatic inactivation in breast and ovarian carcinomas, similar to the results obtained for BRCA1.

Authors
Lancaster, JM; Wooster, R; Mangion, J; Phelan, CM; Cochran, C; Gumbs, C; Seal, S; Barfoot, R; Collins, N; Bignell, G; Patel, S; Hamoudi, R; Larsson, C; Wiseman, RW; Berchuck, A; Iglehart, JD; Marks, JR; Ashworth, A; Stratton, MR; Futreal, PA
MLA Citation
Lancaster, JM, Wooster, R, Mangion, J, Phelan, CM, Cochran, C, Gumbs, C, Seal, S, Barfoot, R, Collins, N, Bignell, G, Patel, S, Hamoudi, R, Larsson, C, Wiseman, RW, Berchuck, A, Iglehart, JD, Marks, JR, Ashworth, A, Stratton, MR, and Futreal, PA. "BRCA2 mutations in primary breast and ovarian cancers." Nat Genet 13.2 (June 1996): 238-240.
PMID
8640235
Source
pubmed
Published In
Nature Genetics
Volume
13
Issue
2
Publish Date
1996
Start Page
238
End Page
240
DOI
10.1038/ng0696-238

M6P/IGF2 receptor: a candidate breast tumor suppressor gene.

The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2r) functions in the activation of TGFbeta, a potent growth inhibitor for most cell types, the degradation of the mitogen, IGF2, and the intracellular trafficking of lysosomal enzymes. We have found its expression to be significantly reduced in both rat and human hepatocellular carcinomas (HCCs) and recently reported loss of heterozygosity (LOH) at this locus with mutations in the remaining allele in human liver tumors. Using the polymerase chain reaction, we utilized two polymorphisms in the 3' untranslated region of M6P/IGF2r to screen breast tumors for LOH. Forty of 62 (65%) patients were informative (heterozygous) and 12/40 (30%) breast tumors had LOH; 5/19 (26%) carcinomas in situ (CIS) and 7/21 (33%) invasive carcinomas. To investigate the early molecular genetic events in breast carcinogenesis, we screened the CIS with LOH for mutations. In 2/5 (40%) of these tumors, missense mutations were found in the remaining allele that gave rise to significant amino acid substitutions. These findings provide evidence that M6P/IGF2r allelic loss is an early event in the etiology of breast cancer, that this gene functions as a tumor suppressor gene in the breast.

Authors
Hankins, GR; De Souza, AT; Bentley, RC; Patel, MR; Marks, JR; Iglehart, JD; Jirtle, RL
MLA Citation
Hankins, GR, De Souza, AT, Bentley, RC, Patel, MR, Marks, JR, Iglehart, JD, and Jirtle, RL. "M6P/IGF2 receptor: a candidate breast tumor suppressor gene." Oncogene 12.9 (May 2, 1996): 2003-2009.
PMID
8649861
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
12
Issue
9
Publish Date
1996
Start Page
2003
End Page
2009

Dominance of wild-type p53-mediated transcriptional activation in breast epithelial cells

The p53 gene is a recessive oncogene whose loss of function can result in cell transformation. Approximately 25% of human breast cancers contain missense mutations in one p53 allele, leading to inactivation of the mutated protein. In almost all of these cases, the wild-type allele is also lost. However, it remains uncertain whether mutant p53 acts in a dominant negative fashion over the wild-type protein. Two parameters of p53 function, transcriptional activation and transcriptional repression, were studied under a variety of experimental conditions within malignant and normal breast epithelial cells. Transient transfection of DNA encoding wild-type p53 was able to transactivate p53-responsive promoters. Wild-type p53 functioned equally well in malignant cells which harbored an endogenous mutation in p53, in malignant cells containing normal p53 and in normal mammary epithelial cells. Co-transfection of cDNAs encoding mutant p53 proteins were unable to inhibit the ability of wild-type p53 to transactivate the reporter constructs. Repression of viral promoters by normal p53 protein was not inhibited transfected mutant p53 proteins. gene WAF1/CIP1/p21 was induced following gamma irradiation in normal mammary cells, containing endogenous wild-type p53 and in the same cells transfected with mutant p53 genes. From these experiments we conclude that mutant p53 proteins do not inactivate the transactivating (or repressing) function of a co-expressed normal p53 protein in these cells implying that complete loss of wild-type p53 is required to eliminate these functions in breast epithelium.

Authors
Davis, P; Bazar, K; Huper, G; Lozano, G; Marks, J; Iglehart, JD
MLA Citation
Davis, P, Bazar, K, Huper, G, Lozano, G, Marks, J, and Iglehart, JD. "Dominance of wild-type p53-mediated transcriptional activation in breast epithelial cells." Oncogene 13.6 (1996): 1315-1322.
PMID
8808706
Source
scival
Published In
Oncogene: Including Oncogene Reviews
Volume
13
Issue
6
Publish Date
1996
Start Page
1315
End Page
1322

Tissue transglutaminase is associated with the neovasculature and extracellular matrix of human breast cancer

Tissue transglutaminase (tTG) is a calcium-dependent enzyme that catalyzes intermolecular covalent bonds. This protein cross-linking activity of tTG stabilizes the extracellular matrix (ECM) by making it resistant proteolytic degradation. Since angiogenesis and tumor cell metastasis require degradation of ECM, we examined the expression of tTG in human breast cancer tissue. We performed immunohistochemistry on twenty-five invasive and non-invasive human breast cancer tissues using a specific monoclonal antibody against the tTG. We found the tTG antigen localized to the boundary between the in situ tumor cells and the normal tissue. Immunohistochemistry also revealed that these cells stained for the endothelial markers, von Willebrand factor, CD31 and CD34 indicating that tTG was present in the neovasculature of the tumor tissue. The tTG antigen was also found in the ECM surrounding the tumor cells in both non-invasive and invasive breast cancer. There was only scattered expression of tTG antigen in five normal mammary tissues studied. We transplanted the R3230AC mammary carcinoma into rats and performed immunohistochemistry. The distribution of tTG in the rodent tumor was similar to that seen in human tissue suggesting that the rodent model will be useful for determining the role of tTG in breast cancer development. In conclusion, we demonstrated that tTG is upregulated in human and rodent breast cancer. The association of tTG with the tumor neovasculature and ECM suesests that tTG mav olav an imoortant role in the orocesses of angiogenesis and metastasis.

Authors
Hetiasch, JM; Haroon, Z; Dewhirst, MW; Marks, J; Iglehart, D; Peters, K; Greenberg, CS
MLA Citation
Hetiasch, JM, Haroon, Z, Dewhirst, MW, Marks, J, Iglehart, D, Peters, K, and Greenberg, CS. "Tissue transglutaminase is associated with the neovasculature and extracellular matrix of human breast cancer." 1996.
Source
scival
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
10
Issue
6
Publish Date
1996
Start Page
A1416

Identification of a new subclass of Alu DNA repeats which can function as estrogen receptor-dependent transcriptional enhancers.

We have utilized a genetic selection system in yeast to identify novel estrogen-responsive genes within the human genome and to define the sequences in the BRCA-1 gene responsible for its estrogen responsiveness. This approach led to the identification of a new subclass within the Alu family of DNA repeats which have diverged from known Alu sequences and have acquired the ability to function as estrogen receptor-dependent enhancers. Importantly, these new elements confer receptor-dependent estrogen responsiveness to a heterologous promoter when assayed in mammalian cells. This transcriptional activity can be attenuated by the addition of either of three different classes of estrogen receptor antagonists, indicating that these elements function as classical estrogen receptor-dependent enhancers. Furthermore, this enhancer activity is restricted to a specific subset of DNA repeats because consensus Alu elements of four major subfamilies do not respond to the estrogen receptor. Previously, most Alu sequences have been considered to be functionally inert. However, this work provides strong evidence that a significant subset can confer estrogen responsiveness upon a promoter within which they are located. Clearly, Alu sequences must now be considered as important contributors to the regulation of gene transcription in estrogen receptor-containing cells.

Authors
Norris, J; Fan, D; Aleman, C; Marks, JR; Futreal, PA; Wiseman, RW; Iglehart, JD; Deininger, PL; McDonnell, DP
MLA Citation
Norris, J, Fan, D, Aleman, C, Marks, JR, Futreal, PA, Wiseman, RW, Iglehart, JD, Deininger, PL, and McDonnell, DP. "Identification of a new subclass of Alu DNA repeats which can function as estrogen receptor-dependent transcriptional enhancers." J Biol Chem 270.39 (September 29, 1995): 22777-22782.
PMID
7559405
Source
pubmed
Published In
The Journal of biological chemistry
Volume
270
Issue
39
Publish Date
1995
Start Page
22777
End Page
22782

Antisense DNA downregulation of the ERBB2 oncogene measured by a flow cytometric assay.

A causal role has been inferred for ERBB2 overexpression in the etiology of breast cancer and other epithelial malignancies. The development of therapeutics that inhibit this tyrosine kinase cell surface receptor remains a high priority. This report describes the specific downregulation of ERBB2 protein and mRNA in the breast cancer cell line SK-BR-3 by using antisense DNA phosphorothioates. An approach was developed to examine antisense effects which allows simultaneous measurements of antisense dose and gene specific regulation on a per cell basis. A fluorescein isothiocyanate end-labeled tracer oligonucleotide was codelivered with antisense DNA followed by immunofluorescent staining for ERBB2 protein expression. Two-color flow cytometry measured the amount of both intracellular oligonucleotide and ERBB2 protein. In addition, populations of cells that received various doses of nucleic acids were physically separated and studied. In any given transfection, a 100-fold variation in oligonucleotide dosage was found. ERBB2 protein expression was reduced greater than 50%, but only in cells within a relatively narrow uptake range. Steady-state ERBB2 mRNA levels were selectively diminished, indicating a specific antisense effect. Cells receiving the optimal antisense dose were sorted and analyzed for cell cycle changes. After 2 days of ERBB2 suppression, breast cancer cells showed an accumulation in the G1 phase of the cell cycle.

Authors
Vaughn, JP; Iglehart, JD; Demirdji, S; Davis, P; Babiss, LE; Caruthers, MH; Marks, JR
MLA Citation
Vaughn, JP, Iglehart, JD, Demirdji, S, Davis, P, Babiss, LE, Caruthers, MH, and Marks, JR. "Antisense DNA downregulation of the ERBB2 oncogene measured by a flow cytometric assay." Proc Natl Acad Sci U S A 92.18 (August 29, 1995): 8338-8342.
PMID
7667291
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
92
Issue
18
Publish Date
1995
Start Page
8338
End Page
8342

Maintenance of DNA content and erbB-2 alterations in intraductal and invasive phases of mammary cancer.

Ductal carcinoma in situ (intraductal carcinoma) of the breast is a commonly recognized and curable clinical entity. Patients with intraductal carcinoma are at risk to develop invasive breast cancer presumably due to a transition from the noninvasive to the invasive phase of growth. Primary breast malignancies commonly display both in situ and invasive phases of growth in the same tumor. In the current study, DNA content and alterations in the erbB-2 (HER-2/neu) oncogene product were examined simultaneously in both growth phases of primary breast cancers by image analysis. DNA content in the intraductal and invasive components of primary breast cancers were virtually identical (r = 0.979, p < 0.001). Quantitative image analysis was used to measure erbB-2 expression and categories of expression were related to copy number of the erbB-2 gene. Expression of erbB-2 was similar in both growth phases and implies identity of the erbB-2 genotype. The identity of DNA content suggests that the noninvasive and invasive phases within a single breast cancer are highly related. It is likely that erbB-2 gene number remains the same during progression from intraductal to invasive disease.

Authors
Iglehart, JD; Kerns, BJ; Huper, G; Marks, JR
MLA Citation
Iglehart, JD, Kerns, BJ, Huper, G, and Marks, JR. "Maintenance of DNA content and erbB-2 alterations in intraductal and invasive phases of mammary cancer." Breast Cancer Res Treat 34.3 (June 1995): 253-263.
PMID
7579490
Source
pubmed
Published In
Breast Cancer Research and Treatment
Volume
34
Issue
3
Publish Date
1995
Start Page
253
End Page
263

Localized adenocarcinoma of the lung: oncogene expression of erbB-2 and p53 in 150 patients.

Historical information and pathological material from 150 consecutive patients with localized adenocarcinoma of the lung was collected to evaluate oncogene expression of erbB-2 and p53, and erbB-2 gene amplification. Pathological material after resection was reviewed to verify histological staging, and patient follow-up was complete in all cases for at least 68 months. Immunohistochemistry of erbB-2 (HER-2/neu) and p53 oncogene expression was performed on two separate paraffin tumor blocks for each patient with normal lung as control. Gene amplification of erbB-2 was measured after DNA extraction from 20-micrometer sections of erbB-2-positive and -negative tumors. All analyses were blinded and included Kaplan-Meier survival estimates with Cox proportional hazards regression modeling. Two adequate blocks of tumor and normal lung were available for 138 (92%) patients. Immunohistochemical identification of expression of p53 was observed in 49 (37%) patients and erbB-2 in 17 (13%) patients. DNA dot blot analyses were performed on 17 erbB-2-positive and 13 randomly selected erbB-2-negative tumors. There was 1 (6%) of 17 erbB-2-positve tumors with 4-fold erbB-2 gene amplification. Actual 5-year survival was 63% and actuarial 10-year survival was 59% for the entire population of 150 patients. Significant univariate predictors (P < 0.05) of cancer death were the presence of symptoms, tumor size >3 cm, poor differentiation, visceral pleural invasion, and p53 expression. Multivariate analysis associated symptoms and p53 expression as independent factors with decreased survival. Thus, this project examined p53 and erbB-2 expression in patients with localized adenocarcinoma and associated p53 status with survival. Multicenter collection of data should allow the development of a model of cancer recurrence in this most common lung cancer.

Authors
Harpole, DH; Marks, JR; Richards, WG; Herndon, JE; Sugarbaker, DJ
MLA Citation
Harpole, DH, Marks, JR, Richards, WG, Herndon, JE, and Sugarbaker, DJ. "Localized adenocarcinoma of the lung: oncogene expression of erbB-2 and p53 in 150 patients." Clin Cancer Res 1.6 (June 1995): 659-664.
PMID
9816029
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
1
Issue
6
Publish Date
1995
Start Page
659
End Page
664

A prognostic model of recurrence and death in stage I non-small cell lung cancer utilizing presentation, histopathology, and oncoprotein expression.

In order to construct a multivariate model for predicting early recurrence and cancer death for patients with stage I non-small cell lung cancer, 271 consecutive patients (mean age, 63 +/- 8 years) who were diagnosed, treated, and followed at one institution were studied. All patients were clinical stage I with head and chest/abdominal computed tomograms and radionuclide bone scans without evidence of metastatic disease. Pathological material after resection was reviewed to verify histological staging. Follow-up documented the time and location of any recurrence, was a median 56 months in duration, and was complete in all cases. Data recorded included age, sex, smoking history, presenting symptoms, pathological description, and oncoprotein staining for erbB-2 (HER-2/neu), p53, and KI-67 proliferation protein. Immunohistochemistry of oncogene expression was performed on two separate archived paraffin tumor blocks for each patient, with normal lung as control. All analyses were blinded and included Kaplan-Meier survival estimates with Cox proportional hazards regression modeling. Data, including immunohistochemistry, were complete for all 271 patients. Actual 5-year survival was 63% and actuarial 10-year survival was 58%. Significant univariate predictors (P < 0.05) of early recurrence and cancer-death were: male sex; the presence of symptoms; chest pain; type of cough; hemoptysis; tumor size > 3 cm diameter (T2); poor differentiation; vascular invasion; erbB-2 expression; p53 expression; and a higher KI-67 proliferation index (> 5%). An additive oncogene expression curve demonstrated a 5-year survival of 72% for 136 patients without p53 or erbB-2, 58% for 108 patients who expressed either oncogene, and 38% for 27 who expressed both (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Harpole, DH; Herndon, JE; Wolfe, WG; Iglehart, JD; Marks, JR
MLA Citation
Harpole, DH, Herndon, JE, Wolfe, WG, Iglehart, JD, and Marks, JR. "A prognostic model of recurrence and death in stage I non-small cell lung cancer utilizing presentation, histopathology, and oncoprotein expression." Cancer Res 55.1 (January 1, 1995): 51-56.
PMID
7805040
Source
pubmed
Published In
Cancer Research
Volume
55
Issue
1
Publish Date
1995
Start Page
51
End Page
56

Simultaneous endometrial malignant mixed mesodermal tumor and ovarian serous adenocarcinoma.

Although simultaneous endometrial and ovarian tumors are observed occasionally, rarely are the two neoplasms histologically disparate. We report a case of simultaneous endometrial malignant mixed mesodermal tumor and ovarian serous adenocarcinoma with a single right external iliac lymph node metastasis. Using immunohistochemical profiles, we demonstrated that the two tumors are separate primary neoplasms and identified the origin of the metastatic deposit as the mixed malignant mesodermal tumor.

Authors
Krigman, HR; Coogan, AC; Marks, JR
MLA Citation
Krigman, HR, Coogan, AC, and Marks, JR. "Simultaneous endometrial malignant mixed mesodermal tumor and ovarian serous adenocarcinoma." Arch Pathol Lab Med 119.1 (January 1995): 99-103.
PMID
7802567
Source
pubmed
Published In
Archives of Pathology and Laboratory Medicine
Volume
119
Issue
1
Publish Date
1995
Start Page
99
End Page
103

GLANDULAR AND STROMAL OVEREXPRESSION OF P53 IN MIXED MALIGNANT MESODERMAL TUMORS (MMMT) - AN ARGUMENT FOR CLONAL ORIGIN

Authors
KRIGMAN, HR; ELBENDARY, A; MARKS, JR
MLA Citation
KRIGMAN, HR, ELBENDARY, A, and MARKS, JR. "GLANDULAR AND STROMAL OVEREXPRESSION OF P53 IN MIXED MALIGNANT MESODERMAL TUMORS (MMMT) - AN ARGUMENT FOR CLONAL ORIGIN." January 1995.
Source
wos-lite
Published In
Laboratory Investigation
Volume
72
Issue
1
Publish Date
1995
Start Page
A92
End Page
A92

Determination of proliferation index by MIB-1 immunostaining in early stage breast cancer using quantitative image analysis

Authors
Layfield, LJ; Kerns, BJ; Conlon, DH; Iglehart, JD; Marks, JR; Dodge, RK
MLA Citation
Layfield, LJ, Kerns, BJ, Conlon, DH, Iglehart, JD, Marks, JR, and Dodge, RK. "Determination of proliferation index by MIB-1 immunostaining in early stage breast cancer using quantitative image analysis." Breast Journal 1.6 (1995): 362-371.
Source
scival
Published In
Breast Journal
Volume
1
Issue
6
Publish Date
1995
Start Page
362
End Page
371

Transforming growth factor beta 1 can induce CIP1/WAF1 expression independent of the p53 pathway in ovarian cancer cells.

Transforming growth factor beta (TGF beta) is an important regulator of cellular proliferation. In normal ovarian epithelial cells, TGF beta acts to inhibit growth. However, in ovarian cancer cell lines, this effect is usually lost. Although the regulatory pathway of TGF beta remains unclear, TGF beta-treated cells arrest late in G1. This inhibition appears to involve blocking of the cyclin-dependent kinase phosphorylation of the retinoblastoma protein. Recently, a general inhibitor of cyclin-dependent kinases, CIP1/WAF1/p21, was identified. Expression of CIP1 is positively regulated by binding of wild-type p53 to a consensus response element upstream of the CIP1 gene. Overexpression of the CIP1 protein causes growth suppression, analogous to TGF beta and wild-type p53. We have examined the induction of CIP1 by TGF beta 1 in ovarian cancer cell lines that have been previously characterized for their proliferative response to TGF beta 1. OVCA420, a cell line that is dramatically growth inhibited by TGF beta 1, significantly induced CIP1 expression in response to TGF beta 1. CIP1 induction was accompanied by a decrease in cdk2 kinase activity and cdk2 protein levels. In three other cell lines that respond weakly to TGF beta 1, CIP1 expression was not induced. To determine if TGF beta 1 induction occurs via p53, regulation of p53 RNA and protein was examined. No differences in p53 transcription, steady-state protein level, de novo synthesis, phosphorylation, or subcellular accumulation were noted. Furthermore, TGF beta 1 could not induce transcription from a consensus p53 DNA binding site in the TGF beta 1-response cell line.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Elbendary, A; Berchuck, A; Davis, P; Havrilesky, L; Bast, RC; Iglehart, JD; Marks, JR
MLA Citation
Elbendary, A, Berchuck, A, Davis, P, Havrilesky, L, Bast, RC, Iglehart, JD, and Marks, JR. "Transforming growth factor beta 1 can induce CIP1/WAF1 expression independent of the p53 pathway in ovarian cancer cells." Cell Growth Differ 5.12 (December 1994): 1301-1307.
PMID
7696178
Source
pubmed
Published In
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research
Volume
5
Issue
12
Publish Date
1994
Start Page
1301
End Page
1307

BRCA1 mutations in primary breast and ovarian carcinomas.

Loss of heterozygosity data from familial tumors suggest that BRCA1, a gene that confers susceptibility to ovarian and early-onset breast cancer, encodes a tumor suppressor. The BRCA1 region is also subject to allelic loss in sporadic breast and ovarian cancers, an indication that BRCA1 mutations may occur somatically in these tumors. The BRCA1 coding region was examined for mutations in primary breast and ovarian tumors that show allele loss at the BRCA1 locus. Mutations were detected in 3 of 32 breast and 1 of 12 ovarian carcinomas; all four mutations were germline alterations and occurred in early-onset cancers. These results suggest that mutation of BRCA1 may not be critical in the development of the majority of breast and ovarian cancers that arise in the absence of a mutant germline allele.

Authors
Futreal, PA; Liu, Q; Shattuck-Eidens, D; Cochran, C; Harshman, K; Tavtigian, S; Bennett, LM; Haugen-Strano, A; Swensen, J; Miki, Y
MLA Citation
Futreal, PA, Liu, Q, Shattuck-Eidens, D, Cochran, C, Harshman, K, Tavtigian, S, Bennett, LM, Haugen-Strano, A, Swensen, J, and Miki, Y. "BRCA1 mutations in primary breast and ovarian carcinomas." Science (New York, N.Y.) 266.5182 (October 1994): 120-122.
PMID
7939630
Source
epmc
Published In
Science
Volume
266
Issue
5182
Publish Date
1994
Start Page
120
End Page
122
DOI
10.1126/science.7939630

Mutation analysis of the THRA1 gene in breast cancer: deletion/fusion of the gene to a novel sequence on 17q in the BT474 cell line.

We have previously described a common region of deletion and allele loss on chromosome 17q in sporadic breast cancers that is likely to contain a tumor suppressor gene. The region, mapped to 17q12-q21, was bordered by D17S250 and D17S579 on the centromeric and telomeric sides, respectively. This deletion region overlaps the BRCA1 locus, which predisposes to familial breast and ovarian cancer. The most frequent loss of heterozygosity was observed at the thyroid hormone receptor alpha (THRA1) locus. Southern analysis revealed a rearrangement of THRA1 in the BT474 breast cancer cell line. This rearrangement represented a deletion of exons 8-10 of one THRA1 allele that was also coamplified with ERBB2. Northern blots showed two mutant transcripts in BT474 cells. Analysis of the mutant transcripts revealed fusion of the THRA1 exon 7 by splicing to a novel sequence designated BTR for "BT474 transcribed rearrangement." BTR was found to be highly conserved and mapped to 17q. The deletion in BT474 cells spans the entire BRCA1 region. To search for additional mutations in the THRA1 gene, all nine protein-encoding exons of THRA1 were examined for point mutations via single strand conformation analysis in a series of primary breast tumors, breast cancer cell lines, and lymphoblastoid cell lines derived from the youngest affected members of several German breast cancer families. No point mutations were detected, including the unrearranged THRA1 allele in BT474. We have thus excluded THRA1 as a commonly mutated sporadic breast cancer tumor suppressor gene and as the BRCA1 gene.

Authors
Futreal, PA; Cochran, C; Marks, JR; Iglehart, JD; Zimmerman, W; Barrett, JC; Wiseman, RW
MLA Citation
Futreal, PA, Cochran, C, Marks, JR, Iglehart, JD, Zimmerman, W, Barrett, JC, and Wiseman, RW. "Mutation analysis of the THRA1 gene in breast cancer: deletion/fusion of the gene to a novel sequence on 17q in the BT474 cell line." Cancer Res 54.7 (April 1, 1994): 1791-1794.
PMID
7511052
Source
pubmed
Published In
Cancer Research
Volume
54
Issue
7
Publish Date
1994
Start Page
1791
End Page
1794

Overexpression of p53 and HER-2/neu proteins as prognostic markers in early stage breast cancer.

OBJECTIVE: Overexpression of the p53 and HER-2/neu oncogenes are the two most common genetic abnormalities associated with breast cancer. Shorter survival time has been reported in patients with tumors with p53 or HER-2/neu. This report analyzes a retrospective cohort of early stage breast cancers for both oncogenes and relates overexpression to clinicopathologic parameters and survival. METHODS: Immunostaining for p53 and HER-2/neu was performed on 230 paraffin-embedded specimens of stage I and II breast cancers diagnosed and treated at Duke University Medical Center between 1984 and 1987. Positive staining for both p53 and HER-2/neu in paraffin-embedded tissues indicates an underlying genetic abnormality: point mutations in the p53 gene and amplification of the HER-2/neu gene. RESULTS: In this cohort of patients, 24% were positive for p53 and 17% for HER-2/neu. Four per cent were positive for both oncogenes. Significant correlations were found between p53 immunostaining and increasing tumor size, stage, and low estrogen and progesterone receptor contents. Univariate analysis showed that p53 and HER-2/neu were indicators of overall and failure-free survival. An additive effect on survival was observed in patients with both oncogene abnormalities. Nodal status, HER-2/neu, and p53 all attained independent prognostic value in a multivariate analysis. CONCLUSIONS: The p53 and HER-2/neu oncogenes have proven but limited prognostic value. An approach that combines several molecular genetic markers with established pathologic criteria may help physicians to make more accurate predictions of prognosis in patients with early stage breast cancer.

Authors
Marks, JR; Humphrey, PA; Wu, K; Berry, D; Bandarenko, N; Kerns, BJ; Iglehart, JD
MLA Citation
Marks, JR, Humphrey, PA, Wu, K, Berry, D, Bandarenko, N, Kerns, BJ, and Iglehart, JD. "Overexpression of p53 and HER-2/neu proteins as prognostic markers in early stage breast cancer." Ann Surg 219.4 (April 1994): 332-341.
PMID
7909221
Source
pubmed
Published In
Annals of Surgery
Volume
219
Issue
4
Publish Date
1994
Start Page
332
End Page
341

Epithelial cells are an important source of tenascin in normal and malignant human breast tissue.

The extracellular matrix glycoprotein tenascin is limited to the periductal matrix of normal breast tissue but is markedly increased in both malignant and fibroadenomatous proliferations. It has been hypothesized that the changes in tenascin expression in these tissues are the result of epithelial induction of tenascin expression by the underlying mesenchyme. We have used Western and Northern blotting techniques to examine tenascin expression by normal and malignant mammary epithelial cells in culture. Normal mammary epithelial cells express tenascin in culture and incorporate the protein into the underlying matrix. The SV40-transformed mammary epithelial cell line HBL100 and some established mammary carcinoma cell lines also express tenascin. In contrast to normal mammary epithelial cells, carcinoma cells incorporate very little tenascin into the underlying matrix. To examine the source of tenascin expression in vivo, we have used in situ hybridization to demonstrate that the epithelial cells are a significant source of tenascin in both normal and malignant breast tissues.

Authors
Lightner, VA; Marks, JR; McCachren, SS
MLA Citation
Lightner, VA, Marks, JR, and McCachren, SS. "Epithelial cells are an important source of tenascin in normal and malignant human breast tissue." Exp Cell Res 210.2 (February 1994): 177-184.
PMID
7507849
Source
pubmed
Published In
Experimental Cell Research
Volume
210
Issue
2
Publish Date
1994
Start Page
177
End Page
184
DOI
10.1006/excr.1994.1027

The p53 tumor suppressor gene frequently is altered in gynecologic cancers.

Mutation of the p53 tumor suppressor gene, often accompanied by overexpression of mutant p53 protein, is the most frequent molecular genetic event described thus far in human cancers. In adenocarcinomas of the ovary and endometrium, p53 overexpression is seen in approximately 10% to 15% of early and 40% to 50% of advanced cancers. Similar to many other types of human cancers, ovarian and endometrial cancers that overexpress p53 protein contain mutations in conserved regions of the p53 gene. These mutations are predominantly transitions, which suggests that they arise spontaneously rather than being caused by carcinogen exposure. Alteration of the p53 gene does not appear to be a feature of endometrial hyperplasias or benign or borderline ovarian tumors. Although mutation and overexpression of p53 rarely occur in cancers of the cervix, vulva, and vagina, it has been shown that human papillomavirus E6 oncoproteins bind to and inactivate p53 protein. Studies of the p53 gene have begun to provide insight into the molecular pathogenesis of gynecologic cancers.

Authors
Berchuck, A; Kohler, MF; Marks, JR; Wiseman, R; Boyd, J; Bast, RC
MLA Citation
Berchuck, A, Kohler, MF, Marks, JR, Wiseman, R, Boyd, J, and Bast, RC. "The p53 tumor suppressor gene frequently is altered in gynecologic cancers." Am J Obstet Gynecol 170.1 Pt 1 (January 1994): 246-252. (Review)
PMID
8296829
Source
pubmed
Published In
American Journal of Obstetrics & Gynecology
Volume
170
Issue
1 Pt 1
Publish Date
1994
Start Page
246
End Page
252

Mutation and overexpression of the p53 tumor suppressor gene frequently occurs in uterine and ovarian sarcomas.

OBJECTIVE: To determine the frequency of mutation and overexpression of the p53 tumor suppressor gene in female genital tract sarcomas. METHODS: Immunostaining for p53 was performed in frozen sections of 46 ovarian and uterine sarcomas. Single-stranded conformation polymorphism analysis of exons 4-9 of the p53 gene was performed in 33 sarcomas. We performed DNA sequencing of the p53 gene in 22 cases in which we found p53 protein overexpression and/or shifted bands on single-stranded conformation polymorphism analysis. RESULTS: Overexpression of p53 was seen in 27 of 46 sarcomas (59%), including 26 of 41 (63%) mixed mesodermal tumors, one of four (25%) leiomyosarcomas, and zero of one endometrial stromal sarcoma. Among the 33 sarcomas subjected to molecular analysis, 21 demonstrated mutations in the p53 gene (64%). Eighteen cancers had a single mutation, whereas three cases showed two mutations in the p53 gene. There was one mutation in exon 4, seven mutations in exon 5, three mutations in exon 6, six mutations in exon 7, six mutations in exon 8, and one mutation in exon 9. With the exception of one microdeletion, which predicted a truncated protein product, all of the mutations were missense point mutations. All but one of the point mutations resulted in changes in the predicted amino acid sequence. There were 18 transition mutations (75%), five transversions (21%), and one deletion (4%). CONCLUSIONS: Mutation of the p53 tumor suppressor gene, with resultant overexpression of p53 protein, frequently occurs in ovarian and uterine sarcomas. Because most of the mutations are transitions, p53 mutations in these cancers likely arise from spontaneous errors in DNA synthesis and repair rather than from exposure to carcinogens.

Authors
Liu, FS; Kohler, MF; Marks, JR; Bast, RC; Boyd, J; Berchuck, A
MLA Citation
Liu, FS, Kohler, MF, Marks, JR, Bast, RC, Boyd, J, and Berchuck, A. "Mutation and overexpression of the p53 tumor suppressor gene frequently occurs in uterine and ovarian sarcomas." Obstet Gynecol 83.1 (January 1994): 118-124.
PMID
8272291
Source
pubmed
Published In
Obstetrics & Gynecology (Elsevier)
Volume
83
Issue
1
Publish Date
1994
Start Page
118
End Page
124

Isolation of a diverged homeobox gene, MOX1, from the BRCA1 region on 17q21 by solution hybrid capture

Using the technique of solution hybridization coupled with magnetic bead capture, we have isolated a novel homeobox-containing gene from the BRCA1 region of 17q21. This gene is the human homologue of the mouse Mox1 gene previously localized to a syntenic region of mouse chromosome 11. Multiple overlapping cDNAs of human MOX1 were identified using both a cosmid and a P1 genomic clone containing the microsatellite markers D17S750 and D17S858 which map within the BRCA1 region defined by D17S776 and D17S78. MOX1 expression was observed in a variety of normal tissues examined, including breast and ovary. Given that the gene contains a homeobox domain and has the potential to regulate growth and differentiation, MOX1 represents an attractive candidate for the BRCA1 gene. This possibility was investigated in a series of BRCA1 kindreds and primary sporadic breast tumors. No evidence for mutation was found in the coding sequence, making it unlikely that MOX1 is the BRCA1 gene. However, the widespread expression of MOX1 in non-embryonal tissues suggests a role in normal cell biology which warrants further study.

Authors
Futreal, PA; Cochran, C; Rosenthal, J; Miki, Y; Swenson, J; Hobbs, M; Bennett, LM; Haugen-Strano, A; Marks, J; Barrett, JC; Tavtigian, SV; Shattuck-Eidens, D; Kamb, A; Skolnick, M; Wiseman, RW
MLA Citation
Futreal, PA, Cochran, C, Rosenthal, J, Miki, Y, Swenson, J, Hobbs, M, Bennett, LM, Haugen-Strano, A, Marks, J, Barrett, JC, Tavtigian, SV, Shattuck-Eidens, D, Kamb, A, Skolnick, M, and Wiseman, RW. "Isolation of a diverged homeobox gene, MOX1, from the BRCA1 region on 17q21 by solution hybrid capture." Human Molecular Genetics 3.8 (1994): 1359-1364.
PMID
7987315
Source
scival
Published In
Human Molecular Genetics
Volume
3
Issue
8
Publish Date
1994
Start Page
1359
End Page
1364

Localization of the VHR phosphatase gene and its analysis as a candidate for BRCA1

The VH1-related human protein (VHR) gene was localized to human chromosome 17q21 in a region thought to contain the BRCA1 locus, a locus that confers susceptibility to breast and ovarian cancer. VHR encodes a phosphatase with dual specificity for tyrosine and serine residues. Thus it is a plausible candidate for a tumor suppressor gene such as BRCA1. To test this possibility, the VHR coding sequence was screened in individuals with familial breast cancer and in sporadic breast tumor and breast cancer cell lines. No mutations were detected, suggesting that the VHR gene is not BRCA1.

Authors
Kamb, A; Futreal, PA; Rosenthal, J; Cochran, C; Harshman, KD; Liu, Q; Phelps, RS; Tavtigian, SV; Tran, T; Hussey, C; Bell, R; Miki, Y; Swensen, J; Hobbs, MR; Marks, J; Bennett, LM; Barrett, JC; Wiseman, RW; Shattuck-Eidens, D
MLA Citation
Kamb, A, Futreal, PA, Rosenthal, J, Cochran, C, Harshman, KD, Liu, Q, Phelps, RS, Tavtigian, SV, Tran, T, Hussey, C, Bell, R, Miki, Y, Swensen, J, Hobbs, MR, Marks, J, Bennett, LM, Barrett, JC, Wiseman, RW, and Shattuck-Eidens, D. "Localization of the VHR phosphatase gene and its analysis as a candidate for BRCA1." Genomics 23.1 (1994): 163-167.
PMID
7829067
Source
scival
Published In
Genomics
Volume
23
Issue
1
Publish Date
1994
Start Page
163
End Page
167
DOI
10.1006/geno.1994.1473

Loss of chromosome 8p sequences in human breast carcinoma cell lines

Cytogenetic and molecular analyses of human breast cancer cells have identified consistent losses of specific chromosomal regions in these tumors, suggesting that such regions harbor tumor suppressor genes whose homozygous loss or inactivation directly contributes to tumorigenesis. To date, deletions of chromosome 8 sequences have been described infrequently and only in low percentages of breast carcinomas. We report the identification of a new DNA marker on chromosome 8p that is deleted in 6 (75%) of 8 breast carcinoma cell lines and in 1 primary breast carcinoma examined. No deletion of this marker was detected in any normal or nonbreast carcinoma cell lines analyzed. Southern blot and fluorescence in situ hybridization studies indicate that this clone maps to chromosome 8 between bands p12 and p21. These observations suggest that a new gene, whose loss or inactivation may foster breast carcinoma tumorigenesis, may reside in this chromosome 8p region. © 1994.

Authors
Pykett, MJ; Murphy, ME; Harnish, PR; Muenke, M; Marks, J; George, DL
MLA Citation
Pykett, MJ, Murphy, ME, Harnish, PR, Muenke, M, Marks, J, and George, DL. "Loss of chromosome 8p sequences in human breast carcinoma cell lines." Cancer Genetics and Cytogenetics 76.1 (1994): 23-28.
PMID
8076345
Source
scival
Published In
Cancer Genetics and Cytogenetics
Volume
76
Issue
1
Publish Date
1994
Start Page
23
End Page
28
DOI
10.1016/0165-4608(94)90064-7

IMMUNODETECTION OF P53 PROTEIN IN NONINVASIVE EPITHELIAL PROLIFERATIVE BREAST DISEASE

Authors
HUMPHREY, PA; FRANQUEMONT, DW; GEARY, WA; KERNS, BJM; IGLEHART, JD; MARKS, JR
MLA Citation
HUMPHREY, PA, FRANQUEMONT, DW, GEARY, WA, KERNS, BJM, IGLEHART, JD, and MARKS, JR. "IMMUNODETECTION OF P53 PROTEIN IN NONINVASIVE EPITHELIAL PROLIFERATIVE BREAST DISEASE." APPLIED IMMUNOHISTOCHEMISTRY 2.1 (1994): 22-28.
Source
wos-lite
Published In
Applied Immunohistochemistry and Molecular Morphology
Volume
2
Issue
1
Publish Date
1994
Start Page
22
End Page
28

Assessment of c-erbB-2 amplification by immunohistochemistry in paraffin-embedded breast cancer.

The c-erbB-2 (HER-2/neu) proto-oncogenes is important in oncogenesis and for determination of prognosis in a number of human malignancies. DNA (Southern) hybridization and immunoblotting (Western) techniques are most commonly utilized for determining amplification status and protein expression of this proto-oncogene, respectively. These extraction techniques are often time-consuming, costly, and subject to variability depending on the histological characteristics of the tumor. Paraffin-immunohistochemistry (P-IHC), on the other hand, is time and cost-effective. In addition, this technique may offer enhanced sensitivity and specificity over extraction techniques due to the in situ nature of analysis. In data presented here, 67 cases of human mammary carcinoma were concomitantly assessed for c-erbB-2 gene copy number and oncoprotein expression by dilutional DNA hybridization and P-IHC, respectively. In 64 (95.5%) of 67 cases, high level expression was associated with gene amplification, whereas no detectable expression was associated with a normal diploid gene copy number. In two of the three discrepant cases, P-IHC predicted amplification not corroborated by Southern analysis. In these cases, tumor mass was limited by the intraductal component of the lesion or by an abundance of stromal elements within the specimen. We conclude that P-IHC offers a favorable alternative to Southern analysis in the assessment of c-erbB-2 gene copy number of this oncoprotein in human mammary carcinoma. Furthermore, immunohistochemistry may prove superior to either extraction technique in specimens with limited tumor mass, such as biopsy materials, stroma-rich tumors, or early stage lesions such as intraductal carcinoma.

Authors
Kerns, BJ; Jordan, PA; Huper, G; Marks, JR; Iglehart, JD; Layfied, LJ
MLA Citation
Kerns, BJ, Jordan, PA, Huper, G, Marks, JR, Iglehart, JD, and Layfied, LJ. "Assessment of c-erbB-2 amplification by immunohistochemistry in paraffin-embedded breast cancer." Mod Pathol 6.6 (November 1993): 673-678.
PMID
7905629
Source
pubmed
Published In
Modern Pathology
Volume
6
Issue
6
Publish Date
1993
Start Page
673
End Page
678

Spectrum of mutation and frequency of allelic deletion of the p53 gene in ovarian cancer.

BACKGROUND: The p53 gene encodes a nuclear phosphoprotein present in low levels in normal human cells. The wild-type form of this protein functions to restrain inappropriate cellular proliferation. Approximately one half of human epithelial ovarian cancers have mutations in the p53 gene and overexpress the mutant protein product. Deletion of one allele of the p53 gene also frequently occurs in these cancers. PURPOSE: We sought to define the spectrum of mutations in the p53 gene in epithelial ovarian cancer with respect to both the specific codons involved and the type of mutations observed. We also examined the frequency of allelic deletion of the p53 gene in cancers containing p53 gene mutations. METHODS: Tissue samples from the epithelial ovarian cancers of 62 patients were obtained during initial laparotomy. Histologic examination was done to ensure that the experimental samples used in this study contained more than 75% cancer cells. Total RNA was extracted from these samples and separately from matched control noncancerous regions of the surgical specimen or white blood cells. The purified RNAs were reverse transcribed to generate cDNA copies of exons 4-10 of the p53 gene. Two rounds of polymerase chain reaction (PCR) were conducted to produce enough template for DNA sequence analysis of the regions of interest within the p53 gene. Dideoxy sequencing of at least two independent productions of each amplified DNA template was done to confirm the validity of the mutations found. Allelic deletions were identified by PCR and gel electrophoretic techniques to examine three polymorphisms within the p53 gene in cancer-normal DNA pairs. RESULTS: We identified 45 mutations in exons 5-8 of the p53 gene, where mutations frequently have been found in other cancer types. An additional mutation was identified in exon 4. Overall, 72% of the mutations were transitions, 24% transversions, and 4% microdeletions. Allelic deletion of the other p53 allele was seen in 67% of ovarian cancers in which a p53 mutation was present. Germ-line p53 mutations were not found in any patients whose cancers had p53 mutations. CONCLUSIONS AND IMPLICATIONS: Like p53 mutations in other types of human cancers, those in epithelial ovarian cancers are diverse and occur frequently in exons 5-8. The predominance of transition mutations suggests that p53 mutations in ovarian cancer arise because of spontaneous errors in DNA synthesis and repair rather than the direct interaction of carcinogens with DNA. These molecular data are consistent with data from epidemiologic studies that have failed to demonstrate a convincing relationship between exposure to environmental carcinogens and the development of ovarian cancer.

Authors
Kohler, MF; Marks, JR; Wiseman, RW; Jacobs, IJ; Davidoff, AM; Clarke-Pearson, DL; Soper, JT; Bast, RC; Berchuck, A
MLA Citation
Kohler, MF, Marks, JR, Wiseman, RW, Jacobs, IJ, Davidoff, AM, Clarke-Pearson, DL, Soper, JT, Bast, RC, and Berchuck, A. "Spectrum of mutation and frequency of allelic deletion of the p53 gene in ovarian cancer." J Natl Cancer Inst 85.18 (September 15, 1993): 1513-1519.
PMID
8360934
Source
pubmed
Published In
Journal of the National Cancer Institute
Volume
85
Issue
18
Publish Date
1993
Start Page
1513
End Page
1519

Mutation of the p53 tumor-suppressor gene is not a feature of endometrial hyperplasias.

OBJECTIVE: Mutation and overexpression of the p53 gene occur in approximately 20% of endometrial carcinomas. To determine whether alteration of the p53 gene is an early event in endometrial carcinogenesis, we examined the p53 gene in endometrial hyperplasias. STUDY DESIGN: Genomic deoxyribonucleic acid was extracted from 117 endometrial hyperplasias (36 simple, 40 complex, 41 atypical) and 30 endometrial cancers. Exons 5 through 8 of the p53 gene were amplified by means of the polymerase chain reaction. Mutations in the p53 gene were sought with single-stranded conformation polymorphism analysis and confirmed by direct deoxyribonucleic acid sequencing. RESULTS: None of 117 endometrial hyperplasias were found to have mutations in the p53 gene, whereas mutations were seen in three of 30 (10%) endometrial cancers (p < 0.02). The p53 mutations seen in three cancers were confirmed by direct sequencing (codons 157, 180, 272). CONCLUSION: Because it does not appear to be a feature of endometrial hyperplasias, mutation of the p53 gene may represent a relatively late event in endometrial carcinogenesis.

Authors
Kohler, MF; Nishii, H; Humphrey, PA; Saski, H; Marks, J; Bast, RC; Clarke-Pearson, DL; Boyd, J; Berchuck, A
MLA Citation
Kohler, MF, Nishii, H, Humphrey, PA, Saski, H, Marks, J, Bast, RC, Clarke-Pearson, DL, Boyd, J, and Berchuck, A. "Mutation of the p53 tumor-suppressor gene is not a feature of endometrial hyperplasias." Am J Obstet Gynecol 169.3 (September 1993): 690-694.
PMID
8372881
Source
pubmed
Published In
American Journal of Obstetrics & Gynecology
Volume
169
Issue
3
Publish Date
1993
Start Page
690
End Page
694

Constitutive production of macrophage colony-stimulating factor and interleukin-6 by human ovarian surface epithelial cells.

Normal and neoplastic epithelial cells produce growth factors that can affect cells from different lineages. Epithelial ovarian cancers produce M-CSF and IL-6. In the present study, production of these cytokines has been measured in the apparently normal epithelial cells from which epithelial ovarian neoplasms are thought to arise. Epithelial cells from the surface of premenopausal human ovaries were established in short-term cultures. The cells bound anti-cytokeratin antibodies and exhibited characteristic epithelial morphology by light and transmission electron microscopy. M-CSF and IL-6 were detected in supernatants from cultures of these cells, using assays specific for each factor. Cytokine levels were comparable to those in supernatants from ovarian and breast cancer cell lines. M-CSF expression could also be demonstrated by immunohistochemical analysis with specific rabbit heteroantiserum. Thus, M-CSF and IL-6 are produced constitutively by normal as well as by neoplastic ovarian epithelium.

Authors
Lidor, YJ; Xu, FJ; Martínez-Maza, O; Olt, GJ; Marks, JR; Berchuck, A; Ramakrishnan, S; Berek, JS; Bast, RC
MLA Citation
Lidor, YJ, Xu, FJ, Martínez-Maza, O, Olt, GJ, Marks, JR, Berchuck, A, Ramakrishnan, S, Berek, JS, and Bast, RC. "Constitutive production of macrophage colony-stimulating factor and interleukin-6 by human ovarian surface epithelial cells." Exp Cell Res 207.2 (August 1993): 332-339.
PMID
8344385
Source
pubmed
Published In
Experimental Cell Research
Volume
207
Issue
2
Publish Date
1993
Start Page
332
End Page
339
DOI
10.1006/excr.1993.1200

Mutation and overexpression of p53 in early-stage epithelial ovarian cancer.

OBJECTIVE: To investigate whether mutation and overexpression of p53 is a feature of early-stage ovarian cancers. METHODS: Because early-stage ovarian cancers are relatively uncommon, we adapted p53 immunostaining and DNA sequencing methods for use in paraffin-embedded tissue blocks. Early-stage ovarian cancers from 52 patients treated at Duke University between 1980-1991 were analyzed. RESULTS: Immunostaining for p53 consistent with overexpression was seen in 29% of early-stage (I/II) ovarian cancers overall. The incidence of p53 overexpression was lower in cancers confined to the ovaries (stage IA/IB) (15%) than in cancers that had spread outside the ovaries (stage IC/II) (44%) (P = .03). Although p53 overexpression was seen more frequently in large tumors (diameter greater than 10 cm) and in tumors with "high-risk" features (stage IC or II, or grade 3), these relationships were not statistically significant. Recurrent disease developed in 35% of the patients in this series, but there was no relationship between p53 overexpression and recurrence rate or survival. The presence of point mutations in the p53 gene was confirmed by DNA sequencing in eight cancers that overexpressed p53. CONCLUSION: Mutation and overexpression of p53 are less frequent in early-stage ovarian cancers than in advanced-stage cases. P53 overexpression is not associated with adverse outcome in early-stage ovarian cancer.

Authors
Kohler, MF; Kerns, BJ; Humphrey, PA; Marks, JR; Bast, RC; Berchuck, A
MLA Citation
Kohler, MF, Kerns, BJ, Humphrey, PA, Marks, JR, Bast, RC, and Berchuck, A. "Mutation and overexpression of p53 in early-stage epithelial ovarian cancer." Obstet Gynecol 81.5 ( Pt 1) (May 1993): 643-650.
PMID
8469448
Source
pubmed
Published In
Obstetrics & Gynecology (Elsevier)
Volume
81
Issue
5 ( Pt 1)
Publish Date
1993
Start Page
643
End Page
650

Clonal origin of epithelial ovarian carcinoma: analysis by loss of heterozygosity, p53 mutation, and X-chromosome inactivation.

BACKGROUND: It has been suggested that multiple sites of epithelial ovarian carcinoma on the peritoneal surface reflect polyclonal disease arising from multiple primary tumors in the peritoneal mesothelium, rather than monoclonal disease spread by metastases from one primary ovarian cancer. PURPOSE: The purpose of this study was to investigate whether ovarian cancer has a monoclonal or polyclonal origin. METHODS: DNA specimens were obtained from peripheral blood lymphocytes (normal DNA) and from multiple tumor deposits of 17 women with epithelial ovarian carcinoma: primary tumors, metastatic deposits, and ascites. The clonal origin of each tumor was determined by performing (a) analysis to detect loss of heterozygosity at five loci on chromosomes 5, 11, 13, and 17; (b) sequencing of exons 5-8 of the p53 gene; and (c) X-chromosome inactivation analysis of the phosphoglycerate kinase (PGK) gene. RESULTS: In 15 of the 17 cases analyzed, there was clear evidence of monoclonal origin. The probability that the genetic events documented in these 15 cases occurred as independent events in each tumor deposit ranged from 2.5 x 10(-1) to 3.7 x 10(-16). In two cases, the pattern of allelic deletion and p53 gene mutation was compatible with either a monoclonal origin or origin from two primary ovarian tumors. CONCLUSIONS: The results did not support the hypothesis that ovarian cancer is a multifocal, polyclonal disease. Instead, the data suggest that sporadic epithelial ovarian carcinoma has either a monoclonal or a dual primary origin. IMPLICATIONS: These findings have important implications for understanding of the natural history of ovarian cancer and for clinical strategies aimed at prevention and early detection. Further studies will be required to determine the clonal origin of familial hereditary ovarian cancer.

Authors
Jacobs, IJ; Kohler, MF; Wiseman, RW; Marks, JR; Whitaker, R; Kerns, BA; Humphrey, P; Berchuck, A; Ponder, BA; Bast, RC
MLA Citation
Jacobs, IJ, Kohler, MF, Wiseman, RW, Marks, JR, Whitaker, R, Kerns, BA, Humphrey, P, Berchuck, A, Ponder, BA, and Bast, RC. "Clonal origin of epithelial ovarian carcinoma: analysis by loss of heterozygosity, p53 mutation, and X-chromosome inactivation." J Natl Cancer Inst 84.23 (December 2, 1992): 1793-1798.
PMID
1433368
Source
pubmed
Published In
Journal of the National Cancer Institute
Volume
84
Issue
23
Publish Date
1992
Start Page
1793
End Page
1798

The effect of interferon gamma on epidermal growth factor receptor expression in normal and malignant ovarian epithelial cells.

OBJECTIVE: We examined the effect of interferon gamma on proliferation and epidermal growth factor receptor expression in ovarian cancer cell lines and normal ovarian epithelial cells. STUDY DESIGN: The tritiated thymidine incorporation assay was used to assess the effect of interferon gamma on proliferation. Scatchard analysis of anti-epidermal growth factor receptor antibody binding, and Western blotting of immunoprecipitates was used to assess the effect of interferon gamma on epidermal growth factor receptor expression. RESULTS: Although interferon gamma elicited 30% to 40% decreases in proliferation, epidermal growth factor receptor expression was strikingly increased in all four ovarian cancer cell lines. Scatchard analysis indicated that this increase occurred primarily at the cell surface, but total cellular receptor levels also were increased. In contrast, interferon gamma treatment of normal ovarian epithelial cells affected neither proliferation nor epidermal growth factor receptor levels. CONCLUSION: Because the up-regulation of epidermal growth factor receptors by interferon gamma appears to be confined to malignant cells, interferon gamma may facilitate immunotherapy and imaging of ovarian cancers by means of immunoconjugates directed against the epidermal growth factor receptor.

Authors
Boente, MP; Berchuck, A; Rodriguez, GC; Davidoff, A; Whitaker, R; Xu, FJ; Marks, J; Clarke-Pearson, DL; Bast, RC
MLA Citation
Boente, MP, Berchuck, A, Rodriguez, GC, Davidoff, A, Whitaker, R, Xu, FJ, Marks, J, Clarke-Pearson, DL, and Bast, RC. "The effect of interferon gamma on epidermal growth factor receptor expression in normal and malignant ovarian epithelial cells." Am J Obstet Gynecol 167.6 (December 1992): 1877-1882.
PMID
1361720
Source
pubmed
Published In
American Journal of Obstetrics & Gynecology
Volume
167
Issue
6
Publish Date
1992
Start Page
1877
End Page
1882

Relative promoter activity in human mammary epithelial cells assayed by transient expression.

Chimeric DNA expression vectors containing regulatory sequences proximal to the 5' end of coding sequences for mammalian genes provide valuable tools to study gene expression. Genes coding for easily measured products (reporter genes) can be used to study promoter strength and regulation of gene expression after transient expression of promoter-reporter constructs in mammalian cells. To determine the strength of a variety of mammalian and viral promoter-enhancer sequences in primary cultures of human mammary epithelial cells (HMEC), these sequences were fused to the bacterial chloramphenicol acetyltransferase (CAT) gene and transfected into HMEC using strontium phosphate. The long terminal repeat (LTR) of the endogenous murine leukemia virus AKR-623 was the most potent promoter of transient CAT expression in HMEC. A number of commonly available promoter sequences displayed a wide range of activities in these cells. The glucocorticoid responsive LTR promoter from the murine mammary tumor virus modulated expression of CAT and was sensitive to the concentration of dexamethasone in the growth media. In a similar fashion, the regulatory sequences from the murine metallothionein-1 gene retained responsiveness to zinc concentration in the growth media.

Authors
Huper, G; Marks, JR; Wiener, JR; Iglehart, JD
MLA Citation
Huper, G, Marks, JR, Wiener, JR, and Iglehart, JD. "Relative promoter activity in human mammary epithelial cells assayed by transient expression." In Vitro Cell Dev Biol 28A.11-12 (November 1992): 730-734.
PMID
1483964
Source
pubmed
Published In
In vitro cellular & developmental biology : journal of the Tissue Culture Association
Volume
28A
Issue
11-12
Publish Date
1992
Start Page
730
End Page
734

p53 overexpression in formalin-fixed, paraffin-embedded tissue detected by immunohistochemistry.

Mutation and overexpression of the p53 gene have been noted in a wide range of human cancers and are thought to play a role in malignant transformation. Previously, immunohistochemical detection of p53 has been possible only in fresh-frozen tissues. We examined p53 expression in paraffin-embedded tissues from 50 epithelial ovarian cancers and 25 primary breast cancers with a modified immunohistochemical (IHC) technique developed in this laboratory, using monoclonal antibody (MAb) PAb1801. The 75 cases were selected from a group of patients in whom the expression levels had already been assessed in a fresh-tissue IHC assay. An identical staining reactivity was observed in both formalin-fixed, paraffin-embedded tissue and fresh-frozen tissue in 48 of 50 (96%) epithelial ovarian cancers and in 23 of 25 (92%) primary breast cancers. Immunodetection of p53 in paraffin-embedded tissue blocks will be a useful alternative to the standard fresh-tissue assay and can accurately reflect the level of p53 expression in human tumors.

Authors
Kerns, BJ; Jordan, PA; Moore, MB; Humphrey, PA; Berchuck, A; Kohler, MF; Bast, RC; Iglehart, JD; Marks, JR
MLA Citation
Kerns, BJ, Jordan, PA, Moore, MB, Humphrey, PA, Berchuck, A, Kohler, MF, Bast, RC, Iglehart, JD, and Marks, JR. "p53 overexpression in formalin-fixed, paraffin-embedded tissue detected by immunohistochemistry." J Histochem Cytochem 40.7 (July 1992): 1047-1051.
PMID
1607637
Source
pubmed
Published In
Journal of Histochemistry and Cytochemistry
Volume
40
Issue
7
Publish Date
1992
Start Page
1047
End Page
1051
DOI
10.1177/40.7.1607637

Detection of frequent allelic loss on proximal chromosome 17q in sporadic breast carcinoma using microsatellite length polymorphisms.

Analyses of losses of heterozygosity and linkage studies have implicated a gene(s) on chromosome 17q in the genesis of sporadic and early-onset familial breast carcinomas, respectively. To define the critical region of 17q, we examined DNAs from a series of 20 sporadic breast carcinomas and corresponding blood samples for allelic losses of chromosome 17q using microsatellite length polymorphisms. With these highly informative markers (average heterozygosity, 0.73), we observed frequent deletions of 17q at several loci. We found that D17S250 was deleted in 50% (7 of 14), THRA1 in 79% (11 of 14), D17S579 in 59% (11 of 19), NME1 in 29% (5 of 17), MPO in 36% (4 of 11), and GH in 25% (4 of 16) in the tumor set examined. A common region of deletion was found that was flanked by D17S250 to D15S579. These markers have recently been localized to a 6-cM interval of proximal chromosome 17q in bands 17q11.2-q21 and map within the region of the early-onset familial breast cancer locus, implying that the same gene or genes may be involved in both sporadic and familial breast tumors. Thyroid hormone receptor alpha and retinoic acid receptor alpha are two potential candidate genes in this region.

Authors
Futreal, PA; Söderkvist, P; Marks, JR; Iglehart, JD; Cochran, C; Barrett, JC; Wiseman, RW
MLA Citation
Futreal, PA, Söderkvist, P, Marks, JR, Iglehart, JD, Cochran, C, Barrett, JC, and Wiseman, RW. "Detection of frequent allelic loss on proximal chromosome 17q in sporadic breast carcinoma using microsatellite length polymorphisms." Cancer Res 52.9 (May 1, 1992): 2624-2627.
PMID
1568230
Source
pubmed
Published In
Cancer Research
Volume
52
Issue
9
Publish Date
1992
Start Page
2624
End Page
2627

Immune response to p53 is dependent upon p53/HSP70 complexes in breast cancers.

Overexpression of the p53 protein, resulting from gene mutations that increase protein stability, has been detected in greater than 25% of primary human breast cancers. In addition, approximately 10% of breast cancer patients have circulating antibodies to the p53 protein. In this study, the anti-p53 humoral response is correlated with the presence and type of mutant p53 protein expressed in the tumor. In a series of 60 breast cancer patients, 0 of 30 tumors with normal, low-level p53 expression induced anti-p53 antibodies, whereas 7 (23%) of 30 tumors with p53 overexpression elicited a specific anti-p53 antibody response. These 7 patients had anti-p53 antibodies that recognized wild-type p53 and a variety of mutant p53 proteins. A comparison of p53 mutations revealed that antibody-negative tumors had mutations exclusively in exons 7 and 8, whereas antibody-positive tumors had mutations primarily in exons 5 and 6. Moreover, all antibody-eliciting tumors contained complexes between p53 and a 70-kDa heat shock protein, whereas none of the antibody-negative tumors contained this complex. This study implicates a 70-kDa heat shock protein in the antigenic presentation of p53.

Authors
Davidoff, AM; Iglehart, JD; Marks, JR
MLA Citation
Davidoff, AM, Iglehart, JD, and Marks, JR. "Immune response to p53 is dependent upon p53/HSP70 complexes in breast cancers." Proc Natl Acad Sci U S A 89.8 (April 15, 1992): 3439-3442.
PMID
1373500
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
89
Issue
8
Publish Date
1992
Start Page
3439
End Page
3442

Overexpression and mutation of p53 in endometrial carcinoma.

Immunohistochemical staining for the p53 protein was performed in 107 snap frozen primary endometrial adenocarcinomas and 15 benign uterine tissues using monoclonal antibody PAb1801. No staining was seen in benign samples, whereas intense nuclear staining of cancer cells consistent with overexpression of the p53 protein was observed in 22 of 107 cancers (21%). p53 overexpression was more frequent in advanced (Stage III/IV) cancers (41%) than in early (Stage I/II) cancers (9%) (P less than 0.001), and also was associated with nonendometrioid histology (P = 0.008), positive peritoneal cytology (P = 0.01), extrauterine metastases (P = 0.003), and negative progesterone receptor status (P = 0.04). To confirm the relationship between p53 overexpression and mutation, p53 mRNA from 8 cancers was reverse transcribed and amplified using the polymerase chain reaction. DNA sequencing revealed point mutations in each of the 5 cancers that overexpressed p53, whereas the wild-type sequence was found in 3 cancers that did not overexpress the protein. Each of the 5 mutations resulted in an amino acid substitution in a highly conserved region of the p53 gene where mutations have been found in other cancers. Further studies are warranted to determine whether the association between p53 overexpression and advanced stage disease is due to accumulation of genetic lesions during tumor progression or whether p53 alterations confer a more virulent phenotype.

Authors
Kohler, MF; Berchuck, A; Davidoff, AM; Humphrey, PA; Dodge, RK; Iglehart, JD; Soper, JT; Clarke-Pearson, DL; Bast, RC; Marks, JR
MLA Citation
Kohler, MF, Berchuck, A, Davidoff, AM, Humphrey, PA, Dodge, RK, Iglehart, JD, Soper, JT, Clarke-Pearson, DL, Bast, RC, and Marks, JR. "Overexpression and mutation of p53 in endometrial carcinoma." Cancer Res 52.6 (March 15, 1992): 1622-1627.
PMID
1540970
Source
pubmed
Published In
Cancer Research
Volume
52
Issue
6
Publish Date
1992
Start Page
1622
End Page
1627

Expression of p53 in human neuroblastoma- and neuroepithelioma-derived cell lines.

Overexpression of the nuclear phosphoprotein p53 has been detected in many different transformed human cell lines and primary adult tumors. Elevated steady-state levels of p53 appear to be the result of an increase in the stability of the protein and, in adult cancers, high levels of the protein are associated with mutation of the p53 gene. In this study, overexpression of p53 was detected in 4 out of 5 human neuroblastoma-derived cell lines. The protein expressed by each of these four lines had a significantly prolonged half-life relative to the p53 protein in immortalized rodent fibroblasts and normal bovine adrenal medullary cells. However, no mutations were detected in the highly conserved regions of the p53 gene in these four neuroblastoma lines and the protein being expressed was not recognized by the mutant-specific anti-p53 monoclonal antibody, PAb 240. Upon retinoic acid-induced differentiation of the LA-N-5 neuroblastoma cell line, the level of p53 protein declined, as did the level of p53 mRNA, but the half-life of the protein remained unchanged. The high level of protein observed in the undifferentiated cell lines appears to result from expression of a stable wild-type p53 protein and increased transcription. In contrast, p53 protein was undetectable in two neuroepithelioma-derived cell lines; the p53 gene in one of these lines contained a nonsense mutation, while the other transcribed truncated p53 mRNA.

Authors
Davidoff, AM; Pence, JC; Shorter, NA; Iglehart, JD; Marks, JR
MLA Citation
Davidoff, AM, Pence, JC, Shorter, NA, Iglehart, JD, and Marks, JR. "Expression of p53 in human neuroblastoma- and neuroepithelioma-derived cell lines." Oncogene 7.1 (January 1992): 127-133.
PMID
1741160
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
7
Issue
1
Publish Date
1992
Start Page
127
End Page
133

p53 alterations in all stages of breast cancer.

Overexpression of the nuclear phosphoprotein p53 is one of the most frequently detected abnormalities in human cancer and appears to be associated with mutation of the p53 gene. In this study of breast cancer, p53 overexpression was detected in two (15%) of 15 pure intraductal tumors, 73 (25%) of 291 primary invasive carcinomas, 13 (50%) of 26 lymph nodes containing metastatic breast cancer, and two of four established breast cancer cell lines. Sequence analysis of selected specimens confirmed that p53 overexpression was associated with mutation of the gene, while no mutations were detected in specimens without p53 overexpression. Thus, overexpression of p53 occurs in all stages of breast cancer and is consistently associated with the production of mutant proteins. Immunohistochemical analysis is a simple method which reliably predicts the presence of most p53 gene mutations in breast cancer specimens.

Authors
Davidoff, AM; Kerns, BJ; Pence, JC; Marks, JR; Iglehart, JD
MLA Citation
Davidoff, AM, Kerns, BJ, Pence, JC, Marks, JR, and Iglehart, JD. "p53 alterations in all stages of breast cancer." J Surg Oncol 48.4 (December 1991): 260-267.
PMID
1745051
Source
pubmed
Published In
Journal of Surgical Oncology
Volume
48
Issue
4
Publish Date
1991
Start Page
260
End Page
267

Proliferation index in various stages of breast cancer determined by Ki-67 immunostaining.

To investigate factors involved in progression of breast cancer, we estimated the growth fraction of malignant cell populations in various stages of mammary cancer growth. Frozen sections were immunostained with the Ki-67 monoclonal antibody and the proliferation index determined using static image analysis. Pure intraductal carcinoma, intraductal carcinoma coexisting with invasive disease, and metastatic sites coexisting with primary tumors were studied. The proliferation index of pure intraductal carcinomas (mean 4.5%, median 1.8%) was not significantly different from invasive mammary cancers (mean 5.1%, median 2.2%). The proliferation index determined for the in situ component of primary cancers (mean 3.8%, median 1.5%) was not significantly different from values obtained from the invasive component of growth (mean 4.2%, median 2.1%). Variability between in situ and invasive components for individual cases was minimal in tumors whose proliferation index was less than 3.0%; for tumors with higher proliferation indices, the differences were greater. However, there was no trend toward a decrease or increase in growth fraction for the two components of primary tumor growth. The mean proliferative index for primary tumors (mean 4.9%, median 4.0%) was not significantly different from the mean proliferative score from a matched group of metastatic sites in the same patients (mean 5.7%, median 5.5%). Comparison of individual cases uncovered differences in some tumors; again no consistent trends in either direction were noted. An increase (or decrease) in growth activity does not accompany the transition from intraductal (in situ) disease to invasive mammary cancer, nor does a change in growth fraction necessarily accompany progression of mammary cancer from the primary to regional metastatic site.

Authors
Pence, JC; Kizilbash, AM; Kerns, BJ; Marks, JR; Iglehart, JD
MLA Citation
Pence, JC, Kizilbash, AM, Kerns, BJ, Marks, JR, and Iglehart, JD. "Proliferation index in various stages of breast cancer determined by Ki-67 immunostaining." J Surg Oncol 48.1 (September 1991): 11-20.
PMID
1716331
Source
pubmed
Published In
Journal of Surgical Oncology
Volume
48
Issue
1
Publish Date
1991
Start Page
11
End Page
20

Relation between p53 overexpression and established prognostic factors in breast cancer.

The nuclear phosphoprotein p53 is expressed in all normal cells and appears to function in cell cycle regulation. Abnormally high levels of the protein are found in many different types of cancer. In breast carcinoma overexpression of p53 is associated with point mutations within highly conserved regions of the p53 gene. These altered genes encode stable p53 proteins that can be detected by standard immunohistochemical techniques unable to detect rapidly degraded wild-type protein. The level of p53 expression in 184 primary breast cancer specimens was assessed by immunohistochemical analysis and related to the following established prognostic factors for breast cancer: age, stage, metastatic involvement, concentration of estrogen and progesterone receptors, proliferative index, and HER-2/neu overexpression. Fifty (27%) of these primary breast cancer specimens had widespread overexpression of p53. Highly significant associations were found between p53 overexpression and late stage, metastatic spread, and low concentration of progesterone receptors. The presence of elevated levels of mutant p53 may itself be a prognostic factor in human breast cancer and activation of this oncogene may be important in the ability of a tumor to metastasize.

Authors
Davidoff, AM; Herndon, JE; Glover, NS; Kerns, BJ; Pence, JC; Iglehart, JD; Marks, JR
MLA Citation
Davidoff, AM, Herndon, JE, Glover, NS, Kerns, BJ, Pence, JC, Iglehart, JD, and Marks, JR. "Relation between p53 overexpression and established prognostic factors in breast cancer." Surgery 110.2 (August 1991): 259-264.
PMID
1858036
Source
pubmed
Published In
Surgery
Volume
110
Issue
2
Publish Date
1991
Start Page
259
End Page
264

Genetic basis for p53 overexpression in human breast cancer.

Overexpression of an activated form of the p53 protein may be involved in neoplastic transformation. We found widespread overexpression of p53 by immunohistochemical staining in 11 (22%) of 49 primary invasive human breast cancers. Northern blot analysis showed that this overexpression was not due to an increase in the steady-state level of p53 mRNA. The p53 gene was directly sequenced in 7 of these tumors with elevated levels of the protein and, in each case, a mutation that altered the coding sequence for p53 was found in a highly conserved region of the gene. Whereas 4 of these tumors contained only a mutant p53 allele, the other 3 tumors exhibited coding sequences from both a mutant and a wild-type allele. p53 mutations have previously been correlated with allelic loss of part of chromosome 17p that contains the p53 locus. Examination of all 49 breast tumors revealed a 61% frequency of deletion at or near the p53 locus. However, the presence of allelic deletion did not correlate with overexpression of the protein. Six tumors that were deleted but did not express high levels of the protein were sequenced and all retained a wild-type p53 allele. In this series of human breast cancers, overexpression of the p53 protein, not allelic loss on chromosome 17p, was always associated with mutation of the p53 gene.

Authors
Davidoff, AM; Humphrey, PA; Iglehart, JD; Marks, JR
MLA Citation
Davidoff, AM, Humphrey, PA, Iglehart, JD, and Marks, JR. "Genetic basis for p53 overexpression in human breast cancer." Proc Natl Acad Sci U S A 88.11 (June 1, 1991): 5006-5010.
PMID
2052583
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
88
Issue
11
Publish Date
1991
Start Page
5006
End Page
5010

Overexpression and mutation of p53 in epithelial ovarian cancer.

We examined p53 expression in 107 epithelial ovarian cancers with immunohistochemical techniques using monoclonal antibody PAb1801. High level expression of nuclear p53 protein was detected in the malignant epithelium in 54 (50%) of these cancers. Expression of p53 protein was undetectable in 13 benign gynecological tissues. p53 mRNA from three cancers that overexpressed the protein were sequenced and point mutations which altered the coding sequence of the highly conserved region of the gene were found in each case. Three cancers with undetectable protein levels also were sequenced and were found to be wild-type through the same region of the gene. As in other cancers, overexpression of the p53 protein in ovarian cancer appears to correlate closely with the presence of mutation in the p53 gene. p53 overexpression did not correlate with stage, histological grade, or the ability to perform optimal cytoreductive surgery. A significant correlation (P = 0.04) was observed between p53 overexpression and aneuploidy in advanced stage (III/IV) disease. There was no significant relationship between overall survival and p53 expression. Since mutation and overexpression of p53 are common in epithelial ovarian cancers, further studies are warranted to clarify the role of p53 in ovarian tumorigenesis.

Authors
Marks, JR; Davidoff, AM; Kerns, BJ; Humphrey, PA; Pence, JC; Dodge, RK; Clarke-Pearson, DL; Iglehart, JD; Bast, RC; Berchuck, A
MLA Citation
Marks, JR, Davidoff, AM, Kerns, BJ, Humphrey, PA, Pence, JC, Dodge, RK, Clarke-Pearson, DL, Iglehart, JD, Bast, RC, and Berchuck, A. "Overexpression and mutation of p53 in epithelial ovarian cancer." Cancer Res 51.11 (June 1, 1991): 2979-2984.
PMID
2032235
Source
pubmed
Published In
Cancer Research
Volume
51
Issue
11
Publish Date
1991
Start Page
2979
End Page
2984

Maintenance of p53 alterations throughout breast cancer progression.

Overexpression of the nuclear phosphoprotein p53 is one of the most common abnormalities in primary human cancer and appears to be due to point mutation within a highly conserved region of the p53 gene which then encodes for a mutant, more stable protein. In this study different stages of breast cancer progression were examined, from in situ to metastatic disease, to determine at what stage mutational activation occurs and whether it is maintained during tumor progression. Two (13%) of 15 pure intraductal tumors expressed high levels of p53 in all malignant epithelial cells. Sequencing of p53 mRNA from one of these tumors demonstrated a nucleotide substitution altering the amino acid composition of the protein. Six (17%) of 35 specimens which contained both in situ and invasive disease expressed high levels of p53. All malignant epithelial cells in these 6 cases stained positively and in no specimen did one component express different levels of the protein than the other growth phase. Sequence analysis of a tissue with significant amounts of both in situ and invasive disease revealed only a single point mutation, without evidence of wild-type nucleotide at the site of substitution, suggesting that p53 mRNA from each component of the tumor contained the same nucleotide substitution. Eleven (50%) of 22 pairs of primary tumors and their lymph node metastases expressed elevated levels of p53, and in each case, expression levels were identical in the primary and secondary sites. Identical mutations were found in the p53 mRNA from two paired primary and metastatic sites. Therefore, mutation within a highly conserved region of the p53 gene leading to overexpression of the protein product can occur in the earliest recognized phase of breast cancer and this alteration is maintained during progression from intraductal to infiltrating carcinoma. Mutations are also conserved during the process of metastatic spread.

Authors
Davidoff, AM; Kerns, BJ; Iglehart, JD; Marks, JR
MLA Citation
Davidoff, AM, Kerns, BJ, Iglehart, JD, and Marks, JR. "Maintenance of p53 alterations throughout breast cancer progression." Cancer Res 51.10 (May 15, 1991): 2605-2610.
PMID
1850660
Source
pubmed
Published In
Cancer Research
Volume
51
Issue
10
Publish Date
1991
Start Page
2605
End Page
2610

Increased erbB-2 gene copies and expression in multiple stages of breast cancer.

In order to examine the role of the erbB-2 oncogene in human breast cancer, gene amplification and expression were examined in multiple stages of tumor progression. Gene amplification ranging from 2-fold to 32-fold was found in 30 (29%) of 130 cases analyzed. Expression of the receptor-like gene product was determined by a combination of Western immunoblotting and immunohistochemistry. In each case of gene amplification, there was high level overexpression (+ + +) of the protein product. In an additional 29 of 111 cases in which expression was studied (26%), there was moderate level overexpression (+ +) of erbB-2 in the absence of gene amplification. Amplification and overexpression of the erbB-2 gene were found in early clinical stages of breast cancer as well as in more advanced cases. In 23 patients, gene number and level of gene expression were equivalent in the primary tumor site compared with single or multiple metastatic sites in regional lymph nodes. Using a combination of immunohistochemistry and in situ cytohybridization, high (+ + +) and moderate (+ +) level overexpression were homogeneously present in all malignant epithelial cells within histological sections of both primary and metastatic tumor. The intraductal component of carcinoma was identified in sections from 16 invasive primary tumors. erbB-2 gene expression in the intraductal lesions was equivalent to or exceeded expression in the infiltrating components of these tumors. Because erbB-2 alterations are (a) present in all clinical stages, (b) maintained during metastatic spread, (c) homogeneously present throughout tumor sections, and (d) present in the in situ as well as infiltrating component, we conclude that these alterations are selected for early and may be important in the initiation of certain mammary cancer.

Authors
Iglehart, JD; Kraus, MH; Langton, BC; Huper, G; Kerns, BJ; Marks, JR
MLA Citation
Iglehart, JD, Kraus, MH, Langton, BC, Huper, G, Kerns, BJ, and Marks, JR. "Increased erbB-2 gene copies and expression in multiple stages of breast cancer." Cancer Res 50.20 (October 15, 1990): 6701-6707.
PMID
2208136
Source
pubmed
Published In
Cancer Research
Volume
50
Issue
20
Publish Date
1990
Start Page
6701
End Page
6707

P53 expression in neuroblastoma

Authors
Davidoff, AM; Pence, JC; Kerns, B-JM; Iglehart, JD; Shorter, NA; Marks, JR
MLA Citation
Davidoff, AM, Pence, JC, Kerns, B-JM, Iglehart, JD, Shorter, NA, and Marks, JR. "P53 expression in neuroblastoma." Surgical Forum 41 (1990): 579-581.
Source
scival
Published In
Surgical Forum
Volume
41
Publish Date
1990
Start Page
579
End Page
581

Impact of the genetic background of transgenic mice upon the formation and timing of choroid plexus papillomas.

Transgenic mice harboring the SV40 large T antigen gene in a C57B1/6J genetic background (SV11) first express this gene at 1-2 weeks of age, develop papillomas of the choroid plexus by 80-90 days, and die within 125 days after birth. Transgenic mice harboring the same transgene in a (SV11-C57Bl/6J x NZW/lacJ) F1 genetic background express considerably lower levels of the transgene mRNA at comparable times after birth. As a consequence, tumor development and death are delayed. The NZW mice appear to contribute a dominant negative regulator for the expression of the SV40 large T antigen transgene, which in turn has a dramatic effect upon the time of appearance of tumors and the death of these transgenic animals.

Authors
Cho, HJ; Seiberg, M; Georgoff, I; Teresky, AK; Marks, JR; Levine, AJ
MLA Citation
Cho, HJ, Seiberg, M, Georgoff, I, Teresky, AK, Marks, JR, and Levine, AJ. "Impact of the genetic background of transgenic mice upon the formation and timing of choroid plexus papillomas." J Neurosci Res 24.1 (September 1989): 115-122.
PMID
2478718
Source
pubmed
Published In
Journal of Neuroscience Research
Volume
24
Issue
1
Publish Date
1989
Start Page
115
End Page
122
DOI
10.1002/jnr.490240116

Cellular gene expression in papillomas of the choroid plexus from transgenic mice that express the simian virus 40 large T antigen.

Transgenic mice that contain the simian virus 40 (SV40) enhancer-promoter and large tumor (T) antigen gene develop papillomas of the choroid plexus. The tumors remain well differentiated on histological examination and express normal levels of tissue-specific mRNAs for transthyretin (TTR) and the 5-HT1C serotonin receptor, two differentiated cell markers. Both Northern (RNA) blot analysis and in situ cytohybridization have been used to monitor the steady-state levels of the mRNAs from the viral oncogene (T antigen) and from several cellular oncogenes. In situ hybridization demonstrated, in serial sections, increased levels of both T antigen mRNA and p53 mRNA localized in the tumor tissue but not in the normal brain tissue. The ratios of the steady-state levels of mRNA for p53/TTR and p53/L32, a ribosomal protein gene, were 2- to 20-fold higher in the tumor tissue than in the normal choroid plexus tissue. Several other oncogenes did not show elevated levels of mRNA in these tumors. p53 protein levels were not detectable in normal brain tissue, but p53 levels were very high in tumor tissue in which all of the p53 was found in a complex with the SV40 large T antigen. These data continue to show a close relationship between SV40 T-antigen-mediated tumorigenesis and the role of p53 in these tumors.

Authors
Marks, JR; Lin, J; Hinds, P; Miller, D; Levine, AJ
MLA Citation
Marks, JR, Lin, J, Hinds, P, Miller, D, and Levine, AJ. "Cellular gene expression in papillomas of the choroid plexus from transgenic mice that express the simian virus 40 large T antigen." J Virol 63.2 (February 1989): 790-797.
PMID
2642978
Source
pubmed
Published In
Journal of virology
Volume
63
Issue
2
Publish Date
1989
Start Page
790
End Page
797

Replication of the murine cytomegalovirus genome: structure and role of the termini in the generation and cleavage of concatenates.

Following infection with murine cytomegalovirus (MCMV), the termini of the linear double-stranded DNA genome fuse to form circular or concatemeric forms which serve as replicative intermediates. To investigate the mechanisms involved in the generation and cleavage of the intracellular concatenates, we have used restriction endonuclease mapping and nucleotide sequence analyses to characterize the structure of the virion DNA termini and intracellular end-to-end fusion fragment. Four each of the cloned EcoRI X and EcoRI c terminal fragments were sequenced. All of the EcoRI X clones and three of the EcoRI c clones contained a 30-base-pair (bp) sequence which was directly repeated at the ends of the MCMV genome. The terminal sequence of the fourth EcoRI c clone began directly after the 30-bp direct repeat. The four EcoRI X clones also had minor length heterogeneity, differing in the number of GC bp at the terminus. Five fusion fragments were sequenced. Three of the fusion fragments contained both direct repeats, while two fusion fragments lacked one entire direct repeat. Direct analyses of the virion DNA and intracellular fusion fragments revealed that the clones accurately reflected the naturally occurring populations and that the relative proportion of fusion fragments containing only one direct repeat increased as the infection progressed. The data suggest that fusion of the termini arises by end-to-end ligation. We also show that adjacent to the MCMV termini are sequences highly conserved among the herpesviruses, and we discuss their potential role in the maturation of the viral genome.

Authors
Marks, JR; Spector, DH
MLA Citation
Marks, JR, and Spector, DH. "Replication of the murine cytomegalovirus genome: structure and role of the termini in the generation and cleavage of concatenates." Virology 162.1 (January 1988): 98-107.
PMID
2827390
Source
pubmed
Published In
Virology
Volume
162
Issue
1
Publish Date
1988
Start Page
98
End Page
107

The expression of viral and cellular genes in papillomas of the choroid plexus induced in transgenic mice.

A line of transgenic mice that carry the SV40 gene for the large Tumor antigen express this protein during the first two weeks of life in brain tissue. By 30-40 days after birth, independently derived multiple foci of abnormal cells appear throughout the choroid plexus. After 90 days, higher levels of T antigen and rapid tumor growth are detected and all these animals die in a narrow time span, between 100-120 days. In situ hybridization with tissue sections and Northern blot analysis have been employed to follow the steady state levels of SV40 RNA and the p53 oncogene RNA levels in normal and tumor tissues. The level of SV40 RNA is quite variable between tumor cells in a section. This heterogeneity of T antigen mRNA levels could permit the selection of cells (from the multiple foci) expressing higher levels of T antigen and growing more rapidly. The increased levels of p53 RNA observed in tumor cells could then result from the active growth state of these cells or a more direct transcriptional activation. Two cellular genes, transthyretin and the 5-HT1C serotonin receptor, both of which are preferentially expressed in normal choroid plexus cells, were also examined for RNA production in these tumors of the choroid plexus. Both of these genes produced high levels of RNA in tumor tissue indicating the retention of well differentiated gene expression in these tumor tissues. This reflects, at the level of gene expression, the well differentiated morphology of these papillomas of the choroid plexus. Interestingly, as cell lines have been derived from these tumors, both the choroid plexus specific RNA species (for 5-HT1C receptor) and characteristic morphology were lost and an increase in T antigen levels was observed.

Authors
Marks, J; Lin, J; Miller, D; Lozano, G; Herbert, J; Levine, AJ
MLA Citation
Marks, J, Lin, J, Miller, D, Lozano, G, Herbert, J, and Levine, AJ. "The expression of viral and cellular genes in papillomas of the choroid plexus induced in transgenic mice." 1988. 163-186.
PMID
2851142
Source
scival
Volume
284
Publish Date
1988
Start Page
163
End Page
186

Relationship between simian virus 40 large tumor antigen expression and tumor formation in transgenic mice.

A line of transgenic mice containing the simian virus 40 (SV40) large tumor antigen gene under the control of the viral enhancer-promoter expressed this viral protein in the brains of these mice within the first 2 weeks after birth. Multiple foci of anaplastic cells formed in the choroid plexuses of these mice at 36 to 41 days after birth, and normal tissue coexisted with these transformed foci. Immunoperoxidase staining to detect the SV40 T antigen showed tumor-specific expression of nuclear T antigen at late times in tumor development, approximately 90 to 100 days and thereafter. The level of SV40 T antigen, on a per cell basis, appeared to be lower in the great majority of choroid plexus cells at earlier times in tumor development. These results suggest that low levels of tumor antigen (14 to 36 days) are present before detectable pathology (36 to 41 days) and the level of T antigen per cell is higher in rapidly growing late-stage tumors (older than 90 days).

Authors
Van Dyke, TA; Finlay, C; Miller, D; Marks, J; Lozano, G; Levine, AJ
MLA Citation
Van Dyke, TA, Finlay, C, Miller, D, Marks, J, Lozano, G, and Levine, AJ. "Relationship between simian virus 40 large tumor antigen expression and tumor formation in transgenic mice." Journal of virology 61.6 (June 1987): 2029-2032.
PMID
3033329
Source
epmc
Published In
Journal of virology
Volume
61
Issue
6
Publish Date
1987
Start Page
2029
End Page
2032

Fusion of the termini of the murine cytomegalovirus genome after infection.

The genome of murine cytomegalovirus, extracted from extracellular virions, is a linear double-stranded DNA molecule ca. 240 kilobase pairs long. In our initial cloning of subgenomic fragments of the murine cytomegalovirus genome, we obtained a HindIII clone which contained fused HindIII-terminal fragments. By hybridizing this cloned DNA fragment to infected-cell DNA, we identified an intracellular restriction fragment which was the length of the sum of the two authentic termini. This fusion fragment was not present in virion DNA but could be detected as early as 2 h postinfection and reached its highest level shortly after the onset of DNA replication at 16 h postinfection. The prereplicative increase of fused ends was not inhibited by a level of phosphonoacetic acid which effectively shut off viral DNA synthesis, nor was the early conversion from free to fused ends prevented by inhibitors of protein or RNA synthesis. The results are consistent with the fused state of viral DNA being a replicative intermediate and precursor to DNA synthesis.

Authors
Marks, JR; Spector, DH
MLA Citation
Marks, JR, and Spector, DH. "Fusion of the termini of the murine cytomegalovirus genome after infection." J Virol 52.1 (October 1984): 24-28.
PMID
6090700
Source
pubmed
Published In
Journal of virology
Volume
52
Issue
1
Publish Date
1984
Start Page
24
End Page
28

Transcription in mouse embryo cells permissively infected by murine cytomegalovirus.

The sites of transcription and abundance of steady-state cytoplasmic viral RNA in murine cytomegalovirus (Smith strain) infected mouse embryo cells were analyzed. Cloned subgenomic DNA fragments were labeled with 32P and hybridized to filters containing polyadenylated RNA extracted from cells at immediate-early, early, and late times in the infection. The pattern of transcription was distinctive at each time point. Immediate-early transcription occurred primarily at 0.770-0.816 map units. Minor sites of immediate-early transcription were clustered at 0.671-0.861 map units and at the termini of the genome (0.944-0.002 map units). Early transcripts were detected from the entire genome with the exception of a fragment at 0.278-0.305 map units. The site of major immediate-early transcription at 0.770-0.816 map units was represented less abundantly while the concentration of RNA from most other sites of immediate-early transcription was increased at the early time point. The most abundant site of early transcription was at 0.840-0.861 map units. RNA from late in the infection hybridized to all subgenomic fragments. The highest concentration of late RNA transcripts was detected with fragments located at 0.444-0.770 map units. In contrast, late RNA transcripts from both ends of the genome were present at a concentration equal to or lower than that seen at the early time point, and the concentration of late RNA from the major early site (0.840-0.861 map units) was significantly decreased. We also detected uninfected mouse cell RNA with three separate subgenomic EcoRI fragments.

Authors
Marks, JR; Mercer, JA; Spector, DH
MLA Citation
Marks, JR, Mercer, JA, and Spector, DH. "Transcription in mouse embryo cells permissively infected by murine cytomegalovirus." Virology 131.1 (November 1983): 247-254.
PMID
6196913
Source
pubmed
Published In
Virology
Volume
131
Issue
1
Publish Date
1983
Start Page
247
End Page
254

Molecular cloning and restriction endonuclease mapping of the murine cytomegalovirus genome (Smith Strain).

We have cloned EcoRI and HindIII fragments of the Smith strain of murine cytomegalovirus (MCMV) in the plasmid vector pACYC184. These cloned fragments were used to establish a restriction endonuclease map of the genome with respect to the EcoRI and HindIII sites. The map was constructed on the basis of data derived from cross-hybridizations of EcoRI and HindIII cloned fragments, double-digestions of the cloned fragments with EcoRI and HindIII, and hybridization of cloned HindIII fragments to Southern blots of MCMV DNA cleaved with EcoRI. From our mapping data, we have determined that the length of the MCMV genome is approximately 240 kbp. The genome does not appear to undergo inversions and lacks detectable repeated sequences. One HindIII cloned fragment was obtained which contained both HindIII termini. The existence of this fragment may be related to the mode of replication of the MCMV genome.

Authors
Mercer, JA; Marks, JR; Spector, DH
MLA Citation
Mercer, JA, Marks, JR, and Spector, DH. "Molecular cloning and restriction endonuclease mapping of the murine cytomegalovirus genome (Smith Strain)." Virology 129.1 (August 1983): 94-106.
PMID
6310888
Source
pubmed
Published In
Virology
Volume
129
Issue
1
Publish Date
1983
Start Page
94
End Page
106
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