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Reihani, Shara

Positions:

Research Program Leader, Sr

Duke Cancer Institute
School of Medicine

Education:

Publications:

Subtype-Specific Radiation Response and Therapeutic Effect of FAS Death Receptor Modulation in Human Breast Cancer.

Breast cancer is the most common malignancy diagnosed among women and represents a heterogeneous group of subtypes. Radiation therapy is a critical component of treatment for breast cancer patients. However, little is known about radiation response among these intrinsic subtypes. In previous studies, we identified a significant induction of FAS after irradiation in biologically favorable breast cancer patients and breast cancer cell lines. Here, we expanded our study and investigated radiation response in a mouse model of breast cancer. MCF7 (luminal), HCC1954 (HER2+) or SUM159 (basal) cells were implanted orthotopically into the dorsal mammary fat pad of nude mice. These mice were then treated with different doses of radiation to assess tumor growth control. We further investigated the therapeutic effect of FAS modulation by silencing FAS in radiation-responsive tumors and injecting FAS agonist antibody into radiation-resistant tumors. Exposure to radiation inhibited MCF7, and to a lesser extent HCC1954 tumor growth in a dose-dependent manner. In contrast, SUM159 tumors were resistant to radiation. The estimated TCD50 values were 19.3 Gy for MCF7 and 44.9 Gy for SUM159. Radiation induced FAS expression in MCF7 tumors, but not SUM159 tumors. We found that silencing of FAS did not negatively impact radiation response in MCF7 tumors, possibly due to compensation by other apoptotic pathways. On the other hand, FAS activating antibody in combination with radiation treatment delayed SUM159 and HCC1954 tumor growth. However, it did not reach statistical significance compared to radiation treatment alone. Our results suggest that there is intrinsic variation in radiation response among breast cancer subtypes. FAS activation concurrent with radiation slows tumor growth in the radiation-resistant subtypes, but the effect was not significant. Alternative subtype-specific modulators of radiation response are under investigation.

Authors
Lee, C-T; Zhou, Y; Roy-Choudhury, K; Siamakpour-Reihani, S; Young, K; Hoang, P; Kirkpatrick, JP; Chi, J-TA; Dewhirst, MW; Horton, JK
MLA Citation
Lee, C-T, Zhou, Y, Roy-Choudhury, K, Siamakpour-Reihani, S, Young, K, Hoang, P, Kirkpatrick, JP, Chi, J-TA, Dewhirst, MW, and Horton, JK. "Subtype-Specific Radiation Response and Therapeutic Effect of FAS Death Receptor Modulation in Human Breast Cancer." Radiation research 188.2 (August 2017): 169-180.
PMID
28598289
Source
epmc
Published In
Radiation Research
Volume
188
Issue
2
Publish Date
2017
Start Page
169
End Page
180
DOI
10.1667/rr14664.1

FAS Death Receptor: A Breast Cancer Subtype-Specific Radiation Response Biomarker and Potential Therapeutic Target.

Although a standardized approach to radiotherapy has been used to treat breast cancer, regardless of subtype (e.g., luminal, basal), recent clinical data suggest that radiation response may vary significantly among subtypes. We hypothesized that this clinical variability may be due, in part, to differences in cellular radiation response. In this study, we utilized RNA samples for microarray analysis from two sources: 1. Paired pre- and postirradiation breast tumor tissue from 32 early-stage breast cancer patients treated in our unique preoperative radiation Phase I trial; and 2. Sixteen biologically diverse breast tumor cell lines exposed to 0 and 5 Gy irradiation. The transcriptome response to radiation exposure was derived by comparing gene expression in samples before and after irradiation. Genes with the highest coefficient of variation were selected for further evaluation and validated at the RNA and protein level. Gene editing and agonistic antibody treatment were performed to assess the impact of gene modulation on radiation response. Gene expression in our cohort of luminal breast cancer patients was distinctly different before and after irradiation. Further, two distinct patterns of gene expression were observed in our biologically diverse group of breast cancer cell lines pre- versus postirradiation. Cell lines that showed significant change after irradiation were largely luminal subtype, while gene expression in the basal and HER2+ cell lines was minimally impacted. The 100 genes with the most significant response to radiation in patients were identified and analyzed for differential patterns of expression in the radiation-responsive versus nonresponsive cell lines. Fourteen genes were identified as significant, including FAS, a member of the tumor necrosis factor receptor family known to play a critical role in programed cell death. Modulation of FAS in breast cancer cell lines altered radiation response phenotype and enhanced radiation sensitivity in radioresistant basal cell lines. Our findings suggest that cell-type-specific, radiation-induced FAS contributes to subtype-specific breast cancer radiation response and that activation of FAS pathways may be exploited for biologically tailored radiotherapy.

Authors
Horton, JK; Siamakpour-Reihani, S; Lee, C-T; Zhou, Y; Chen, W; Geradts, J; Fels, DR; Hoang, P; Ashcraft, KA; Groth, J; Kung, H-N; Dewhirst, MW; Chi, J-TA
MLA Citation
Horton, JK, Siamakpour-Reihani, S, Lee, C-T, Zhou, Y, Chen, W, Geradts, J, Fels, DR, Hoang, P, Ashcraft, KA, Groth, J, Kung, H-N, Dewhirst, MW, and Chi, J-TA. "FAS Death Receptor: A Breast Cancer Subtype-Specific Radiation Response Biomarker and Potential Therapeutic Target." Radiation research 184.5 (November 2015): 456-469.
PMID
26488758
Source
epmc
Published In
Radiation Research
Volume
184
Issue
5
Publish Date
2015
Start Page
456
End Page
469
DOI
10.1667/rr14089.1

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

Exercise behavior and patient-reported outcomes in women with early breast cancer receiving locoregional radiation therapy.

Radiation therapy is associated with acute treatment-related complications that can lead to decreased quality of life (QOL). Exercise has been shown in other cancer treatment settings to improve negative outcomes. We conducted a prospective pilot study to explore the association between exercise, patient-reported outcomes, and acute radiation therapy toxicities.Women receiving curative breast radiation therapy were enrolled. Each patient completed an exercise behavior/QOL survey before or during the first week of treatment and again during the last week of treatment. Exercise behavior was quantified with the Godin Leisure Time Exercise Questionnaire (metabolic equivalent [MET] hours per week). Measurements to evaluate upper extremity lymphedema and shoulder range of motion were completed. Skin toxicity was assessed weekly. Patient-reported outcomes were measured using standardized questionnaires.Forty-five patients were enrolled. Mean patient age was 54 (range, 28-73) years. Mean METs in the exercise cohort (≥9 METs/wk) was 21 per week (range, 11-38, n = 14); 3 per week (range, 0-8, n = 25) in the nonexercise cohort (<9 METs/wk). Women in the exercise cohort showed improvements in treatment-induced quality of life and fatigue (not significant) despite more extensive surgical, medical, and radiation treatment. No differences in treatment-related toxicities, pain, or sleep scores were noted. Lymphedema was mild (<3 cm) in the entire patient cohort.The vast majority of current exercise oncology literature implicates physical activity as an independent predictor of QOL in cancer patients. Our study noted similar trends, but they were not statistically significant. This may be due to our finding that patient-reported outcomes with radiation therapy are relatively high compared with other treatment modalities and remain stable throughout treatment. Thus, it may be that radiation therapy has a limited impact on QOL in breast cancer patients. Exercise may be best used as a targeted therapy in patients at high risk for poor QOL or radiation-related toxicities at baseline.

Authors
Arya, R; Siamakpour-Reihani, S; Palta, M; Massa, L; Broadwater, G; Blitzblau, RC; Horton, JK
MLA Citation
Arya, R, Siamakpour-Reihani, S, Palta, M, Massa, L, Broadwater, G, Blitzblau, RC, and Horton, JK. "Exercise behavior and patient-reported outcomes in women with early breast cancer receiving locoregional radiation therapy." Practical radiation oncology 5.4 (July 2015): e275-e281.
PMID
25731964
Source
epmc
Published In
Practical Radiation Oncology
Volume
5
Issue
4
Publish Date
2015
Start Page
e275
End Page
e281
DOI
10.1016/j.prro.2015.01.003

Preoperative Single-Fraction Partial Breast Radiation Therapy: A Novel Phase 1, Dose-Escalation Protocol With Radiation Response Biomarkers.

Women with biologically favorable early-stage breast cancer are increasingly treated with accelerated partial breast radiation (PBI). However, treatment-related morbidities have been linked to the large postoperative treatment volumes required for external beam PBI. Relative to external beam delivery, alternative PBI techniques require equipment that is not universally available. To address these issues, we designed a phase 1 trial utilizing widely available technology to 1) evaluate the safety of a single radiation treatment delivered preoperatively to the small-volume, intact breast tumor and 2) identify imaging and genomic markers of radiation response.Women aged ≥55 years with clinically node-negative, estrogen receptor-positive, and/or progesterone receptor-positive HER2-, T1 invasive carcinomas, or low- to intermediate-grade in situ disease ≤2 cm were enrolled (n=32). Intensity modulated radiation therapy was used to deliver 15 Gy (n=8), 18 Gy (n=8), or 21 Gy (n=16) to the tumor with a 1.5-cm margin. Lumpectomy was performed within 10 days. Paired pre- and postradiation magnetic resonance images and patient tumor samples were analyzed.No dose-limiting toxicity was observed. At a median follow-up of 23 months, there have been no recurrences. Physician-rated cosmetic outcomes were good/excellent, and chronic toxicities were grade 1 to 2 (fibrosis, hyperpigmentation) in patients receiving preoperative radiation only. Evidence of dose-dependent changes in vascular permeability, cell density, and expression of genes regulating immunity and cell death were seen in response to radiation.Preoperative single-dose radiation therapy to intact breast tumors is well tolerated. Radiation response is marked by early indicators of cell death in this biologically favorable patient cohort. This study represents a first step toward a novel partial breast radiation approach. Preoperative radiation should be tested in future clinical trials because it has the potential to challenge the current treatment paradigm and provide a path forward to identify radiation response biomarkers.

Authors
Horton, JK; Blitzblau, RC; Yoo, S; Geradts, J; Chang, Z; Baker, JA; Georgiade, GS; Chen, W; Siamakpour-Reihani, S; Wang, C; Broadwater, G; Groth, J; Palta, M; Dewhirst, M; Barry, WT; Duffy, EA; Chi, J-TA; Hwang, ES
MLA Citation
Horton, JK, Blitzblau, RC, Yoo, S, Geradts, J, Chang, Z, Baker, JA, Georgiade, GS, Chen, W, Siamakpour-Reihani, S, Wang, C, Broadwater, G, Groth, J, Palta, M, Dewhirst, M, Barry, WT, Duffy, EA, Chi, J-TA, and Hwang, ES. "Preoperative Single-Fraction Partial Breast Radiation Therapy: A Novel Phase 1, Dose-Escalation Protocol With Radiation Response Biomarkers." International journal of radiation oncology, biology, physics 92.4 (July 2015): 846-855.
PMID
26104938
Source
epmc
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
92
Issue
4
Publish Date
2015
Start Page
846
End Page
855
DOI
10.1016/j.ijrobp.2015.03.007

Genomic profiling in locally advanced and inflammatory breast cancer and its link to DCE-MRI and overall survival.

We have previously reported that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion patterns obtained from locally advanced breast cancer (LABC) patients prior to neoadjuvant therapy predicted pathologic clinical response. Genomic analyses were also independently conducted on the same patient population. This retrospective study was performed to test two hypotheses: (1) gene expression profiles are associated with DCE-MRI perfusion patterns, and (2) association between long-term overall survival data and gene expression profiles can lead to the identification of novel predictive biomarkers.We utilised RNA microarray and DCE-MRI data from 47 LABC patients, including 13 inflammatory breast cancer (IBC) patients. Association between gene expression profile and DCE-MRI perfusion patterns (centrifugal and centripetal) was determined by Wilcoxon rank sum test. Association between gene expression level and survival was assessed using a Cox rank score test. Additional genomic analysis of the IBC subset was conducted, with a period of follow-up of up to 11 years. Associations between gene expression and overall survival were further assessed in The Cancer Genome Atlas Data Portal.Differences in gene expression profiles were seen between centrifugal and centripetal perfusion patterns in the sulphotransferase family, cytosolic, 1 A, phenol-preferring, members 1 and 2 (SULT1A1, SULT1A2), poly (ADP-ribose) polymerase, member 6 (PARP6), and metastasis tumour antigen1 (MTA1). In the IBC subset our analyses demonstrated that differential expression of 45 genes was associated with long-term survival.Here we have demonstrated an association between DCE-MRI perfusion patterns and gene expression profiles. In addition we have reported on candidate prognostic biomarkers in IBC patients, with some of the genes being significantly associated with survival in IBC and LABC.

Authors
Siamakpour-Reihani, S; Owzar, K; Jiang, C; Scarbrough, PM; Craciunescu, OI; Horton, JK; Dressman, HK; Blackwell, KL; Dewhirst, MW
MLA Citation
Siamakpour-Reihani, S, Owzar, K, Jiang, C, Scarbrough, PM, Craciunescu, OI, Horton, JK, Dressman, HK, Blackwell, KL, and Dewhirst, MW. "Genomic profiling in locally advanced and inflammatory breast cancer and its link to DCE-MRI and overall survival." International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 31.4 (June 2015): 386-395.
PMID
25811737
Source
epmc
Published In
International Journal of Hyperthermia (Informa)
Volume
31
Issue
4
Publish Date
2015
Start Page
386
End Page
395
DOI
10.3109/02656736.2015.1016557

Differential Angiogenic Gene Expression in TP53 Wild-Type and Mutant Ovarian Cancer Cell Lines.

Underlying mechanisms regulating angiogenesis in ovarian cancer have not been completely elucidated. Evidence suggests that the TP53 tumor suppressor pathway and tumor microenvironment play integral roles. We utilized microarray technology to study the interaction between TP53 mutational status and hypoxia on angiogenic gene expression.Affymetrix U133A arrays were analyzed for angiogenic gene expression in 19 ovarian cancer cell lines stratified both by TP53 mutation status and A2780 wild-type (wt) TP53 vs. mutated (m) TP53 cell lines after treatment under hypoxic conditions or with ionizing radiation.Twenty-eight differentially expressed angiogenic genes were identified in the mTP53 cell lines compared to wtTP53 lines. Five genes were upregulated in mTP53 cells: 40% involved in extracellular matrix (ECM) degradation [matrix metalloproteinase 10 (MMP10)/15] and 60% in angiogenesis (fibroblast growth factor receptor 3/VEGFA/ephrin receptor-B4). Twenty-three genes were upregulated in wtTP53: nearly 22% were ECM constituents or involved in ECM degradation; over 40% were growth factors or mediators of angiogenesis. Five genes were upregulated in the A2780mTP53 cells: 40% involved in ECM remodeling (MMP10, ADAMTS1), 40% with pro-angiogenic activity (EFNB2, factor 2 receptor), and 20% with anti-angiogenic properties (ADAMTS1). Three genes were upregulated in hypoxia treated cells compared to controls: one with anti-angiogenic activity (angiopoietin-like 4) and two with pro-angiogenic activity (VEGFA, EFNA3). No significant gene fold changes were noted after exposure to radiation. Four genes continued to demonstrate significant differential expression (p ≤ 0.05) after adjusting for multiple comparisons. These genes included endoglin upregulation in wt lines (pro-angiogenesis) and upregulation of FGF20 (growth factor), ADAMTS1 (anti-angiogenesis) and MMP10 (ECM degradation) in mTP53 cell lines.Our exploratory findings indicate that non-overlapping angiogenic pathways may be altered by TP53 mutations and hypoxic conditions in the tumor microenvironment. Further evaluation is needed for confirmation.

Authors
Davidson, BA; Rubatt, JM; Corcoran, DL; Teoh, DK; Bernardini, MQ; Grace, LA; Soper, WJ; Berchuck, A; Siamakpour-Reihani, S; Chen, W; Owzar, K; Murphy, SK; Secord, AA
MLA Citation
Davidson, BA, Rubatt, JM, Corcoran, DL, Teoh, DK, Bernardini, MQ, Grace, LA, Soper, WJ, Berchuck, A, Siamakpour-Reihani, S, Chen, W, Owzar, K, Murphy, SK, and Secord, AA. "Differential Angiogenic Gene Expression in TP53 Wild-Type and Mutant Ovarian Cancer Cell Lines." Frontiers in oncology 4 (January 2014): 163-.
PMID
24999452
Source
epmc
Published In
Frontiers in Oncology
Volume
4
Publish Date
2014
Start Page
163
DOI
10.3389/fonc.2014.00163

Grb7 binds to Hax-1 and undergoes an intramolecular domain association that offers a model for Grb7 regulation.

Adaptor proteins mediate signal transduction from cell surface receptors to downstream signaling pathways. The Grb7 protein family of adaptor proteins is constituted by Grb7, Grb10, and Grb14. This protein family has been shown to be overexpressed in certain cancers and cancer cell lines. Grb7-mediated cell migration has been shown to proceed through a focal adhesion kinase (FAK)/Grb7 pathway, although the specific participants downstream of Grb7 in cell migration signaling have not been fully determined. In this study, we report that Grb7 interacts with Hax-1, a cytoskeletal-associated protein found overexpressed in metastatic tumors and cancer cell lines. Additionally, in yeast 2-hybrid assays, we show that the interaction is specific to the Grb7-RA and -PH domains. We have also demonstrated that full-length Grb7 and Hax-1 interact in mammalian cells and that Grb7 is tyrosine phosphorylated. Isothermal titration calorimetry measurements demonstrate the Grb7-RA-PH domains bind to the Grb7-SH2 domain with micromolar affinity, suggesting full-length Grb7 can exist in a head-to-tail conformational state that could serve a self-regulatory function.

Authors
Siamakpour-Reihani, S; Peterson, TA; Bradford, AM; Argiros, HJ; Haas, LL; Lor, SN; Haulsee, ZM; Spuches, AM; Johnson, DL; Rohrschneider, LR; Shuster, CB; Lyons, BA
MLA Citation
Siamakpour-Reihani, S, Peterson, TA, Bradford, AM, Argiros, HJ, Haas, LL, Lor, SN, Haulsee, ZM, Spuches, AM, Johnson, DL, Rohrschneider, LR, Shuster, CB, and Lyons, BA. "Grb7 binds to Hax-1 and undergoes an intramolecular domain association that offers a model for Grb7 regulation." Journal of molecular recognition : JMR 24.2 (March 2011): 314-321.
PMID
20665473
Source
epmc
Published In
Journal of Molecular Recognition
Volume
24
Issue
2
Publish Date
2011
Start Page
314
End Page
321
DOI
10.1002/jmr.1062

Secreted frizzle-related protein 2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway.

Secreted frizzle-related protein 2 (SFRP2), a modulator of Wnt signaling, has recently been found to be overexpressed in the vasculature of 85% of human breast tumors; however, its role in angiogenesis is unknown. We found that SFRP2 induced angiogenesis in the mouse Matrigel plug assay and the chick chorioallantoic membrane assay. SFRP2 inhibited hypoxia induced endothelial cell apoptosis, increased endothelial cell migration, and induced endothelial tube formation. The canonical Wnt pathway was not affected by SFRP2 in endothelial cells; however, a component of the noncanonical Wnt/Ca2+ pathway was affected by SFRP2 as shown by an increase in NFATc3 in the nuclear fraction of SFRP2-treated endothelial cells. Tacrolimus, a calcineurin inhibitor that inhibits dephosphorylation of NFAT, inhibited SFRP2-induced endothelial tube formation. Tacrolimus 3 mg/kg/d inhibited the growth of SVR angiosarcoma xenografts in mice by 46% (P = 0.04). In conclusion, SFRP2 is a novel stimulator of angiogenesis that stimulates angiogenesis via a calcineurin/NFAT pathway and may be a favorable target for the inhibition of angiogenesis in solid tumors.

Authors
Courtwright, A; Siamakpour-Reihani, S; Arbiser, JL; Banet, N; Hilliard, E; Fried, L; Livasy, C; Ketelsen, D; Nepal, DB; Perou, CM; Patterson, C; Klauber-Demore, N
MLA Citation
Courtwright, A, Siamakpour-Reihani, S, Arbiser, JL, Banet, N, Hilliard, E, Fried, L, Livasy, C, Ketelsen, D, Nepal, DB, Perou, CM, Patterson, C, and Klauber-Demore, N. "Secreted frizzle-related protein 2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway." Cancer research 69.11 (June 2009): 4621-4628.
PMID
19458075
Source
epmc
Published In
Cancer Research
Volume
69
Issue
11
Publish Date
2009
Start Page
4621
End Page
4628
DOI
10.1158/0008-5472.can-08-3402
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