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Alvarez, James Valerinano

Positions:

Assistant Professor of Pharmacology & Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 1999

B.S. — Pennsylvania State University

Ph.D. 2005

Ph.D. — Harvard Medical School

Grants:

Par-4 Regulation and Function in Breast Cancer Dormancy and Recurrence

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2016
End Date
June 30, 2021

Publications:

Oncogene pathway activation in mammary tumors dictates FDG-PET uptake.

Increased glucose utilization is a hallmark of human cancer that is used to image tumors clinically. In this widely used application, glucose uptake by tumors is monitored by positron emission tomography of the labeled glucose analogue 2[(18)F]fluoro-2-deoxy-D-glucose (FDG). Despite its widespread clinical use, the cellular and molecular mechanisms that determine FDG uptake--and that underlie the heterogeneity observed across cancers-remain poorly understood. In this study, we compared FDG uptake in mammary tumors driven by the Akt1, c-MYC, HER2/neu, Wnt1, or H-Ras oncogenes in genetically engineered mice, correlating it to tumor growth, cell proliferation, and expression levels of gene involved in key steps of glycolytic metabolism. We found that FDG uptake by tumors was dictated principally by the driver oncogene and was not independently associated with tumor growth or cellular proliferation. Oncogene downregulation resulted in a rapid decrease in FDG uptake, preceding effects on tumor regression, irrespective of the baseline level of uptake. FDG uptake correlated positively with expression of hexokinase-2 (HK2) and hypoxia-inducible factor-1α (HIF1α) and associated negatively with PFK-2b expression and p-AMPK. The correlation between HK2 and FDG uptake was independent of all variables tested, including the initiating oncogene, suggesting that HK2 is an independent predictor of FDG uptake. In contrast, expression of Glut1 was correlated with FDG uptake only in tumors driven by Akt or HER2/neu. Together, these results demonstrate that the oncogenic pathway activated within a tumor is a primary determinant of its FDG uptake, mediated by key glycolytic enzymes, and provide a framework to interpret effects on this key parameter in clinical imaging.

Authors
Alvarez, JV; Belka, GK; Pan, T-C; Chen, C-C; Blankemeyer, E; Alavi, A; Karp, JS; Chodosh, LA
MLA Citation
Alvarez, JV, Belka, GK, Pan, T-C, Chen, C-C, Blankemeyer, E, Alavi, A, Karp, JS, and Chodosh, LA. "Oncogene pathway activation in mammary tumors dictates FDG-PET uptake." Cancer research 74.24 (December 2014): 7583-7598.
PMID
25239452
Source
epmc
Published In
Cancer Research
Volume
74
Issue
24
Publish Date
2014
Start Page
7583
End Page
7598
DOI
10.1158/0008-5472.can-14-1235

SPSB1 promotes breast cancer recurrence by potentiating c-MET signaling.

Breast cancer mortality is principally due to tumor recurrence; however, the molecular mechanisms underlying this process are poorly understood. We now demonstrate that the suppressor of cytokine signaling protein SPSB1 is spontaneously upregulated during mammary tumor recurrence and is both necessary and sufficient to promote tumor recurrence in genetically engineered mouse models. The recurrence-promoting effects of SPSB1 result from its ability to protect cells from apoptosis induced by HER2/neu pathway inhibition or chemotherapy. This, in turn, is attributable to SPSB1 potentiation of c-MET signaling, such that preexisting SPSB1-overexpressing tumor cells are selected for following HER2/neu downregulation. Consistent with this, SPSB1 expression is positively correlated with c-MET activity in human breast cancers and with an increased risk of relapse in patients with breast cancer in a manner that is dependent upon c-MET activity. Our findings define a novel pathway that contributes to breast cancer recurrence and provide the first evidence implicating SPSB proteins in cancer.The principal cause of death from breast cancer is recurrence. This study identifies SPSB1 as a critical mediator of breast cancer recurrence, suggests activation of the SPSB1-c-MET pathway as an important mechanism of therapeutic resistance in breast cancers, and emphasizes that pharmacologic targets for recurrence may be unique to this stage of tumor progression.

Authors
Feng, Y; Pan, T-C; Pant, DK; Chakrabarti, KR; Alvarez, JV; Ruth, JR; Chodosh, LA
MLA Citation
Feng, Y, Pan, T-C, Pant, DK, Chakrabarti, KR, Alvarez, JV, Ruth, JR, and Chodosh, LA. "SPSB1 promotes breast cancer recurrence by potentiating c-MET signaling." Cancer discovery 4.7 (July 2014): 790-803.
PMID
24786206
Source
epmc
Published In
Cancer Discovery
Volume
4
Issue
7
Publish Date
2014
Start Page
790
End Page
803
DOI
10.1158/2159-8290.cd-13-0548

Par-4 downregulation promotes breast cancer recurrence by preventing multinucleation following targeted therapy.

Most deaths from breast cancer result from tumor recurrence, but mechanisms underlying tumor relapse are largely unknown. We now report that Par-4 is downregulated during tumor recurrence and that Par-4 downregulation is necessary and sufficient to promote recurrence. Tumor cells with low Par-4 expression survive therapy by evading a program of Par-4-dependent multinucleation and apoptosis that is otherwise engaged following treatment. Low Par-4 expression is associated with poor response to neoadjuvant chemotherapy and an increased risk of relapse in patients with breast cancer, and Par-4 is downregulated in residual tumor cells that survive neoadjuvant chemotherapy. Our findings identify Par-4-induced multinucleation as a mechanism of cell death in oncogene-addicted cells and establish Par-4 as a negative regulator of breast cancer recurrence.

Authors
Alvarez, JV; Pan, T-C; Ruth, J; Feng, Y; Zhou, A; Pant, D; Grimley, JS; Wandless, TJ; Demichele, A; Chodosh, LA
MLA Citation
Alvarez, JV, Pan, T-C, Ruth, J, Feng, Y, Zhou, A, Pant, D, Grimley, JS, Wandless, TJ, Demichele, A, and Chodosh, LA. "Par-4 downregulation promotes breast cancer recurrence by preventing multinucleation following targeted therapy." Cancer cell 24.1 (July 2013): 30-44.
PMID
23770012
Source
epmc
Published In
Cancer Cell
Volume
24
Issue
1
Publish Date
2013
Start Page
30
End Page
44
DOI
10.1016/j.ccr.2013.05.007

Autocrine prolactin induced by the Pten-Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways.

Extrapituitary prolactin (Prl) is produced in humans and rodents; however, little is known about its in vivo regulation or physiological function. We now report that autocrine prolactin is required for terminal mammary epithelial differentiation during pregnancy and that its production is regulated by the Pten-PI3K-Akt pathway. Conditional activation of the PI3K-Akt pathway in the mammary glands of virgin mice by either Akt1 expression or Pten deletion rapidly induced terminal mammary epithelial differentiation accompanied by the synthesis of milk despite the absence of lobuloalveolar development. Surprisingly, we found that mammary differentiation was due to the PI3K-Akt-dependent synthesis and secretion of autocrine prolactin and downstream activation of the prolactin receptor (Prlr)-Jak-Stat5 pathway. Consistent with this, Akt-induced mammary differentiation was abrogated in Prl(-/-), Prlr(-/-), and Stat5(-/-) mice. Furthermore, cells treated with conditioned medium from mammary glands in which Akt had been activated underwent rapid Stat5 phosphorylation in a manner that was blocked by inhibition of Jak2, treatment with an anti-Prl antibody, or deletion of the prolactin gene. Demonstrating a physiological requirement for autocrine prolactin, mammary glands from lactation-defective Akt1(-/-);Akt2(+/-) mice failed to express autocrine prolactin or activate Stat5 during late pregnancy despite normal levels of circulating serum prolactin and pituitary prolactin production. Our findings reveal that PI3K-Akt pathway activation is necessary and sufficient to induce autocrine prolactin production in the mammary gland, Stat5 activation, and terminal mammary epithelial differentiation, even in the absence of the normal developmental program that prepares the mammary gland for lactation. Together, these findings identify a function for autocrine prolactin during normal development and demonstrate its endogenous regulation by the PI3K-Akt pathway.

Authors
Chen, C-C; Stairs, DB; Boxer, RB; Belka, GK; Horseman, ND; Alvarez, JV; Chodosh, LA
MLA Citation
Chen, C-C, Stairs, DB, Boxer, RB, Belka, GK, Horseman, ND, Alvarez, JV, and Chodosh, LA. "Autocrine prolactin induced by the Pten-Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways." Genes & development 26.19 (October 2012): 2154-2168.
PMID
23028142
Source
epmc
Published In
Genes & development
Volume
26
Issue
19
Publish Date
2012
Start Page
2154
End Page
2168
DOI
10.1101/gad.197343.112

Oncogene addiction: Mouse models and clinical relevance for molecularly targeted therapies

© 2012, Springer Science+Business Media, LLC. All rights reserved.Cancer results from the dysregulation of pathways controlling the growth, proliferation, differentiation, and survival of tumor cells, as well as fundamental alterations in the manner in which cells interact with their microenvironment (Hanahan and Weinberg 2000). Several lines of evidence suggest that these alterations are due to the accumulation of multiple mutations in oncogenes and tumor suppressor genes that disrupt their normal function or regulation. These mutations provide a selective advantage to the cells in which they occur, leading to their expansion and clinical manifestation as a tumor.

Authors
Alvarez, JV; Yeh, ES; Feng, Y; Chodosh, LA
MLA Citation
Alvarez, JV, Yeh, ES, Feng, Y, and Chodosh, LA. "Oncogene addiction: Mouse models and clinical relevance for molecularly targeted therapies." (January 1, 2012): 527-547. (Chapter)
Source
scopus
Publish Date
2012
Start Page
527
End Page
547
DOI
10.1007/978-0-387-69805-2_25

Akt is required for Stat5 activation and mammary differentiation.

The Akt pathway plays a central role in regulating cell survival, proliferation and metabolism, and is one of the most commonly activated pathways in human cancer. A role for Akt in epithelial differentiation, however, has not been established. We previously reported that mice lacking Akt1, but not Akt2, exhibit a pronounced metabolic defect during late pregnancy and lactation that results from a failure to upregulate Glut1 as well as several lipid synthetic enzymes. Despite this metabolic defect, however, both Akt1-deficient and Akt2-deficient mice exhibit normal mammary epithelial differentiation and Stat5 activation.In light of the overlapping functions of Akt family members, we considered the possibility that Akt may play an essential role in regulating mammary epithelial development that is not evident in Akt1-deficient mice due to compensation by other Akt isoforms. To address this possibility, we interbred mice bearing targeted deletions in Akt1 and Akt2 and determined the effect on mammary differentiation during pregnancy and lactation.Deletion of one allele of Akt2 in Akt1-deficient mice resulted in a severe defect in Stat5 activation during late pregnancy that was accompanied by a global failure of terminal mammary epithelial cell differentiation, as manifested by the near-complete loss in production of the three principal components of milk: lactose, lipid, and milk proteins. This defect was due, in part, to a failure of pregnant Akt1(-/-);Akt2(+/-) mice to upregulate the positive regulator of Prlr-Jak-Stat5 signaling, Id2, or to downregulate the negative regulators of Prlr-Jak-Stat5 signaling, caveolin-1 and Socs2.Our findings demonstrate an unexpected requirement for Akt in Prlr-Jak-Stat5 signaling and establish Akt as an essential central regulator of mammary epithelial differentiation and lactation.

Authors
Chen, C-C; Boxer, RB; Stairs, DB; Portocarrero, CP; Horton, RH; Alvarez, JV; Birnbaum, MJ; Chodosh, LA
MLA Citation
Chen, C-C, Boxer, RB, Stairs, DB, Portocarrero, CP, Horton, RH, Alvarez, JV, Birnbaum, MJ, and Chodosh, LA. "Akt is required for Stat5 activation and mammary differentiation." Breast cancer research : BCR 12.5 (January 2010): R72-.
PMID
20849614
Source
epmc
Published In
Breast Cancer Research
Volume
12
Issue
5
Publish Date
2010
Start Page
R72
DOI
10.1186/bcr2640

Akt is required for Stat5 activation and mammary differentiation.

The Akt pathway plays a central role in regulating cell survival, proliferation and metabolism, and is one of the most commonly activated pathways in human cancer. A role for Akt in epithelial differentiation, however, has not been established. We previously reported that mice lacking Akt1, but not Akt2, exhibit a pronounced metabolic defect during late pregnancy and lactation that results from a failure to upregulate Glut1 as well as several lipid synthetic enzymes. Despite this metabolic defect, however, both Akt1-deficient and Akt2-deficient mice exhibit normal mammary epithelial differentiation and Stat5 activation. In light of the overlapping functions of Akt family members, we considered the possibility that Akt may play an essential role in regulating mammary epithelial development that is not evident in Akt1-deficient mice due to compensation by other Akt isoforms. To address this possibility, we interbred mice bearing targeted deletions in Akt1 and Akt2 and determined the effect on mammary differentiation during pregnancy and lactation. Deletion of one allele of Akt2 in Akt1-deficient mice resulted in a severe defect in Stat5 activation during late pregnancy that was accompanied by a global failure of terminal mammary epithelial cell differentiation, as manifested by the near-complete loss in production of the three principal components of milk: lactose, lipid, and milk proteins. This defect was due, in part, to a failure of pregnant Akt1(-/-);Akt2(+/-) mice to upregulate the positive regulator of Prlr-Jak-Stat5 signaling, Id2, or to downregulate the negative regulators of Prlr-Jak-Stat5 signaling, caveolin-1 and Socs2. Our findings demonstrate an unexpected requirement for Akt in Prlr-Jak-Stat5 signaling and establish Akt as an essential central regulator of mammary epithelial differentiation and lactation.

Authors
Chen, C-C; Boxer, RB; Stairs, DB; Portocarrero, CP; Horton, RH; Alvarez, JV; Birnbaum, MJ; Chodosh, LA
MLA Citation
Chen, C-C, Boxer, RB, Stairs, DB, Portocarrero, CP, Horton, RH, Alvarez, JV, Birnbaum, MJ, and Chodosh, LA. "Akt is required for Stat5 activation and mammary differentiation." Breast cancer research : BCR 12.5 (2010): R72-.
Source
scival
Published In
Breast Cancer Research
Volume
12
Issue
5
Publish Date
2010
Start Page
R72
DOI
10.1186/bcr2640

Singular value decomposition-based regression identifies activation of endogenous signaling pathways in vivo.

The ability to detect activation of signaling pathways based solely on gene expression data represents an important goal in biological research. We tested the sensitivity of singular value decomposition-based regression by focusing on functional interactions between the Ras and transforming growth factor beta signaling pathways. Our findings demonstrate that this approach is sufficiently sensitive to detect the secondary activation of endogenous signaling pathways as it occurs through crosstalk following ectopic activation of a primary pathway.

Authors
Liu, Z; Wang, M; Alvarez, JV; Bonney, ME; Chen, C-C; D'Cruz, C; Pan, T-C; Tadesse, MG; Chodosh, LA
MLA Citation
Liu, Z, Wang, M, Alvarez, JV, Bonney, ME, Chen, C-C, D'Cruz, C, Pan, T-C, Tadesse, MG, and Chodosh, LA. "Singular value decomposition-based regression identifies activation of endogenous signaling pathways in vivo." Genome biology 9.12 (January 2008): R180-.
PMID
19094238
Source
epmc
Published In
Genome Biology: biology for the post-genomic era
Volume
9
Issue
12
Publish Date
2008
Start Page
R180
DOI
10.1186/gb-2008-9-12-r180

mILC-ing the mouse mammary gland: A model for invasive lobular carcinoma.

Mouse models that faithfully recapitulate human cancers are indispensable tools for studying the molecular mechanisms of tumorigenesis and testing potential anticancer therapies. In this issue of Cancer Cell, Derksen et al. describe a new mouse model that mimics multiple features of invasive lobular carcinoma of the breast (ILC), a histological subtype of human breast cancer for which no mouse model currently exists. This model further reveals an important causal link between E-cadherin loss and tumor initiation and metastasis and, in doing so, provides a valuable entrée into the tumor-suppressive functions of E-cadherin as well as the molecular underpinnings of ILC.

Authors
Alvarez, JV; Perez, D; Chodosh, LA
MLA Citation
Alvarez, JV, Perez, D, and Chodosh, LA. "mILC-ing the mouse mammary gland: A model for invasive lobular carcinoma." Cancer cell 10.5 (November 2006): 347-349.
PMID
17097555
Source
epmc
Published In
Cancer Cell
Volume
10
Issue
5
Publish Date
2006
Start Page
347
End Page
349
DOI
10.1016/j.ccr.2006.10.016

Cyclin D1 overexpression and response to bortezomib treatment in a breast cancer model.

BACKGROUND: Cyclin D1 is frequently overexpressed in breast cancer, and its overexpression is, surprisingly, associated with improved survival. One potential mechanism for this association involves signal transducer and activator of transcription 3 (STAT3). METHODS: Cyclin D1 and STAT3 expression were assessed in human tumors using microarray analysis and in breast cancer cell lines HBL100, T47D, MCF7, MDA-MB-453, and BT20 and in HBL100 and T47D cells stably overexpressing cyclin D1 using immunoblot analysis. Cyclin D1 protein was stabilized by treatment with the proteasome inhibitor bortezomib, and the effects on STAT3 expression in vitro was determined by using immunoblotting and on xenograft tumor growth and apoptosis in vivo was determined by using terminal deoxyuridine nick-end labeling assays. All statistical tests were two-sided. RESULTS: Tumors with high cyclin D1 expression (n = 17) had low STAT3 expression (mean = 274 arbitrary units), and those with low cyclin D1 expression (n = 31) had high STAT3 expression (mean = 882 arbitrary units) (P<.001). In HBL100 and T47D parental and cyclin D1-overexpressing cells, cyclin D1 overexpression was also inversely associated with STAT3 expression, and cyclin D1 directly reduced the expression of STAT3. Stabilization of cyclin D1 protein by bortezomib treatment further amplified the cyclin D1-dependent repression of STAT3 in vitro and slowed tumor growth in vivo (week 7: untreated mean = 185.7 mm3 versus treated mean = 136.2 mm3, difference = 49.5 mm3, 95% confidence interval [CI] = 18 to 81 mm3, P = .007; week 8: untreated mean = 240.2 mm3 versus treated mean = 157.3 mm3, difference = 82.9 mm3, 95% CI = 9.1 to 156.7 mm3, P = .0014; and week 9: untreated mean = 256.4 mm3 versus treated mean = 170.2 mm3, difference = 86.2 mm3, 95% CI = 22.8 to 149.6 mm3, P = .006) and increased apoptosis (untreated mean = 19% versus treated mean = 54%, difference = 35%, 95% CI = 24.7% to 45.4%; P = .013) of xenograft tumors. CONCLUSIONS: Cyclin D1 repression of STAT3 expression may explain the association between cyclin D1 overexpression and improved outcome in breast cancer. In addition, bortezomib can amplify the proapoptotic function of cyclin D1, raising the possibility that cyclin D1 levels may be a marker for predicting the response to this novel drug.

Authors
Ishii, Y; Pirkmaier, A; Alvarez, JV; Frank, DA; Keselman, I; Logothetis, D; Mandeli, J; O'Connell, MJ; Waxman, S; Germain, D
MLA Citation
Ishii, Y, Pirkmaier, A, Alvarez, JV, Frank, DA, Keselman, I, Logothetis, D, Mandeli, J, O'Connell, MJ, Waxman, S, and Germain, D. "Cyclin D1 overexpression and response to bortezomib treatment in a breast cancer model." Journal of the National Cancer Institute 98.17 (September 2006): 1238-1247.
PMID
16954476
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
98
Issue
17
Publish Date
2006
Start Page
1238
End Page
1247
DOI
10.1093/jnci/djj334

Tyrosine phosphorylation is required for functional activation of disulfide-containing constitutively active STAT mutants.

Aberrant activation of STAT transcription factors has been implicated in a variety of cancers. Constitutively active forms of STAT1 and STAT3 (STAT1C and STAT3C) have been developed to determine the effects of STAT activation in isolation from other cytokine-stimulated signaling pathways. These mutants were created by engineering cysteine residues into the carboxy terminus of each STAT molecule, allowing a hypothesized disulfide bond to form between two unphosphorylated monomers. To determine whether the presence of cysteine residues is sufficient to allow for functional activation in the absence of tyrosine phosphorylation, we developed STAT1C and STAT3C mutants that are unable to be phosphorylated on the critical tyrosine residue. Without the tyrosine residue, cysteine containing constitutive STAT mutants failed to transactivate STAT target genes. Furthermore, transfection of STAT dominant negative mutants prevented the activation of STAT1C and STAT3C. Cytokine-induced activation of STAT1C and STAT3C was dramatically prolonged when compared to wild-type proteins and led to extended STAT-dependent gene activation. These data show that tyrosine phosphorylation is required for activation of STAT1C and STAT3C. Additionally, these findings suggest the existence of basal phosphorylation that is a dynamic process that involves both phosphorylation and dephosphorylation. The constitutive STAT mutants likely show heightened activity because of the cysteine residues stabilizing these dimers and preventing dephosphorylation, resulting in the accumulation of trancriptionally active STAT dimer complexes.

Authors
Liddle, FJ; Alvarez, JV; Poli, V; Frank, DA
MLA Citation
Liddle, FJ, Alvarez, JV, Poli, V, and Frank, DA. "Tyrosine phosphorylation is required for functional activation of disulfide-containing constitutively active STAT mutants." Biochemistry 45.17 (May 2006): 5599-5605.
PMID
16634641
Source
epmc
Published In
Biochemistry
Volume
45
Issue
17
Publish Date
2006
Start Page
5599
End Page
5605
DOI
10.1021/bi0525674

Signal transducer and activator of transcription 3 is required for the oncogenic effects of non-small-cell lung cancer-associated mutations of the epidermal growth factor receptor.

Somatic mutations in the epidermal growth factor receptor (EGFR) occur frequently in lung cancer and confer sensitivity to EGFR kinase inhibitors gefitinib and erlotinib. These mutations, which occur in the kinase domain of the protein, also render EGFR constitutively active and transforming. Signal transducers and activators of transcription 3 (STAT3) transduces signals from a number of oncogenic tyrosine kinases and contributes to a wide spectrum of human malignancies. Here, we show that STAT3 is activated by mutant EGFRs and is necessary for its downstream phenotypic effects. Inhibiting STAT3 function in fibroblasts abrogates transformation by mutant EGFR. In non-small-cell lung cancer cells, STAT3 activity is regulated by EGFR through modulation of STAT3 serine phosphorylation. Inhibiting STAT3 function increases apoptosis of these cells, suggesting that STAT3 is necessary for their survival. Finally, a group of genes constituting a STAT3 signature is enriched in lung tumors with EGFR mutations. Thus, STAT3 is a critical mediator of the oncogenic effects of somatic EGFR mutations and targeting STAT3 may be an effective strategy for treating tumors characterized by these mutations.

Authors
Alvarez, JV; Greulich, H; Sellers, WR; Meyerson, M; Frank, DA
MLA Citation
Alvarez, JV, Greulich, H, Sellers, WR, Meyerson, M, and Frank, DA. "Signal transducer and activator of transcription 3 is required for the oncogenic effects of non-small-cell lung cancer-associated mutations of the epidermal growth factor receptor." Cancer research 66.6 (March 2006): 3162-3168.
PMID
16540667
Source
epmc
Published In
Cancer Research
Volume
66
Issue
6
Publish Date
2006
Start Page
3162
End Page
3168
DOI
10.1158/0008-5472.can-05-3757

Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants.

Somatic mutations in the kinase domain of the epidermal growth factor receptor tyrosine kinase gene EGFR are common in lung adenocarcinoma. The presence of mutations correlates with tumor sensitivity to the EGFR inhibitors erlotinib and gefitinib, but the transforming potential of specific mutations and their relationship to drug sensitivity have not been described.Here, we demonstrate that EGFR active site mutants are oncogenic. Mutant EGFR can transform both fibroblasts and lung epithelial cells in the absence of exogenous epidermal growth factor, as evidenced by anchorage-independent growth, focus formation, and tumor formation in immunocompromised mice. Transformation is associated with constitutive autophosphorylation of EGFR, Shc phosphorylation, and STAT pathway activation. Whereas transformation by most EGFR mutants confers on cells sensitivity to erlotinib and gefitinib, transformation by an exon 20 insertion makes cells resistant to these inhibitors but more sensitive to the irreversible inhibitor CL-387,785.Oncogenic transformation of cells by different EGFR mutants causes differential sensitivity to gefitinib and erlotinib. Treatment of lung cancers harboring EGFR exon 20 insertions may therefore require the development of alternative kinase inhibition strategies.

Authors
Greulich, H; Chen, T-H; Feng, W; Jänne, PA; Alvarez, JV; Zappaterra, M; Bulmer, SE; Frank, DA; Hahn, WC; Sellers, WR; Meyerson, M
MLA Citation
Greulich, H, Chen, T-H, Feng, W, Jänne, PA, Alvarez, JV, Zappaterra, M, Bulmer, SE, Frank, DA, Hahn, WC, Sellers, WR, and Meyerson, M. "Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants." PLoS medicine 2.11 (November 2005): e313-.
PMID
16187797
Source
epmc
Published In
PLoS medicine
Volume
2
Issue
11
Publish Date
2005
Start Page
e313
DOI
10.1371/journal.pmed.0020313

Identification of a genetic signature of activated signal transducer and activator of transcription 3 in human tumors.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is activated in diverse human tumors and may play a direct role in malignant transformation. However, the full complement of target genes that STAT3 regulates to promote oncogenesis is not known. We created a system to express a constitutively active form of STAT3, STAT3-C, in mouse fibroblasts and used it to identify STAT3 targets. We showed that a subset of these targets, which include transcription factors regulating cell growth, survival, and differentiation, are coexpressed in a range of human tumors. Using immunohistochemical staining of tissue microarrays, we showed that these targets are enriched in breast and prostate tumors harboring activated STAT3. Finally, we showed that STAT3 is required for the expression of these genes in a breast cancer cell line. Taken together, these results identify a cohort of STAT3 targets that may mediate its role in oncogenesis.

Authors
Alvarez, JV; Febbo, PG; Ramaswamy, S; Loda, M; Richardson, A; Frank, DA
MLA Citation
Alvarez, JV, Febbo, PG, Ramaswamy, S, Loda, M, Richardson, A, and Frank, DA. "Identification of a genetic signature of activated signal transducer and activator of transcription 3 in human tumors." Cancer research 65.12 (June 2005): 5054-5062.
PMID
15958548
Source
epmc
Published In
Cancer Research
Volume
65
Issue
12
Publish Date
2005
Start Page
5054
End Page
5062
DOI
10.1158/0008-5472.can-04-4281

Isolation of unique STAT5 targets by chromatin immunoprecipitation-based gene identification.

STAT5a and STAT5b are two highly related transcription factors that control essential cellular functions. Several STAT5 targets are known, although it is likely that most remain uncharacterized. To identify a more complete set of STAT5-regulated genes, we used a modification of the chromatin immunoprecipitation procedure, which does not presuppose any information regarding these targets. Employing Ba/f3 cells in which STAT5 is activated by interleukin-3, we have identified novel STAT5 binding sites that may be regulatory regions for nearby genes. These sites are typically found far from transcription start sites, and most do not contain CpG islands, indicating that they are not in traditional promoter regions. Nonetheless, when the expression of genes near these STAT5 binding sites was examined, all were expressed in Ba/f3 cells, and most were modulated by interleukin-3. Furthermore, genes identified by this strategy show unique expression patterns in acute leukemias, tumors characterized by activated STAT5. Whereas both STAT5 isoforms bound to all promoters tested, STAT5a and STAT5b bound with different kinetics, suggesting that at least some of the differences between the functions of these two proteins are mediated by their DNA binding activity. Therefore, this method of transcription factor target identification represents an effective strategy to isolate transcription factor targets in an unbiased fashion, and it has revealed many novel STAT5-dependent regulatory regions outside of traditional promoters.

Authors
Nelson, EA; Walker, SR; Alvarez, JV; Frank, DA
MLA Citation
Nelson, EA, Walker, SR, Alvarez, JV, and Frank, DA. "Isolation of unique STAT5 targets by chromatin immunoprecipitation-based gene identification." The Journal of biological chemistry 279.52 (December 2004): 54724-54730.
PMID
15498775
Source
epmc
Published In
The Journal of biological chemistry
Volume
279
Issue
52
Publish Date
2004
Start Page
54724
End Page
54730
DOI
10.1074/jbc.m408464200

Genome-wide analysis of STAT target genes: elucidating the mechanism of STAT-mediated oncogenesis.

Inappropriate activation of transcription factors is a common event in cancer. These transcription factors contribute to a malignant phenotype by regulating genes involved in cellular proliferation, survival, differentiation, angiogenesis, and invasion. An important goal remains identifying the targets of oncogenic transcription factors that execute these changes. STAT proteins are among the best-studied of these transcription factors, and are involved in oncogenesis both in vivo and in vitro. They thus represent an ideal model for understanding how transcription factors cause cancer through coordinated changes in gene expression. Recent studies have employed microarray-based expression analysis to comprehensively identify STAT target genes. Analysis of these targets can provide insight into mechanisms of neoplastic transformation, and may shed light on new strategies for targeted therapy.

Authors
Alvarez, JV; Frank, DA
MLA Citation
Alvarez, JV, and Frank, DA. "Genome-wide analysis of STAT target genes: elucidating the mechanism of STAT-mediated oncogenesis." Cancer biology & therapy 3.11 (November 22, 2004): 1045-1050.
PMID
15539936
Source
epmc
Published In
Cancer Biology and Therapy
Volume
3
Issue
11
Publish Date
2004
Start Page
1045
End Page
1050
DOI
10.4161/cbt.3.11.1172
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