Abstract B30: Estrogen-ERβ axis: Implications for racial disparity of prostate cancer.

Introduction: The roles of estrogens and estrogen receptors (ERs) in the disproportionate incidence and mortality of prostate cancer (PCa) among African Americans (AA) as opposed to Caucasian Americans (CA) have not been established. Although estrogens have been shown to be involved in normal and pathologic growth of prostate gland including prostate cancer (PCa). Because ERα and ERβ are different in terms of ligand binding, heterodimerization, transactivation, and estrogen response element activity, their aberrant expression may act as a key factor to determine the ultimate estrogen effects on prostate cancer cells. Although recent studies have reported a role for ERβ in PCa, its ethnic-based expression and underlying mechanisms are not fully understood. Methods: Differential expression of ERβ was assessed using an NCI-designed ethnicity-based tissue microarray (TMA) slide encompassing 150 each of AA and CA prostate cancer tissue cores, 17 BPH, 13 normal biopsies, and 3 PCa cell lines (LNCaP, DU-145 and PC-3). In another set of experiments, androgen dependent (LNCaP) and independent (C4-2B and PC-3) cell lines were treated with various concentrations (up to 10 nM) of dihydrotestosterone (DHT) and estradiol (E2). Cell proliferation, expression of hormone receptors (qPCR and Western blot analysis), and crosstalk of AR and ERs transactivation using specific pharmacologic inhibitors and ERα and ERβ shRNA-stable-transfected COS-7 cells in presence or absence of hormones were performed. Results: In comparison to normal subjects, circulating E2 levels were significantly elevated (p=0.016) in all PCa patients. Further analysis demonstrates an increase in circulating E2 levels in AA (p=0.002) in comparison to CA men with PCa. Histoscore analysis demonstrates intense nuclear immunoreactivity (p=0.002) for ERβ in tumor cores of AA than in CA men. The biracial expression of ERβ was validated by qRT-PCR on LCM-procured tumor cells (p=0.032). Adjusted multivariate analysis showed a positive correlation (p<0.042) between ERβ expression and the age at diagnosis in AA men. However, no correlation found between ERβ and other clinical parameters in CA men. At the molecular level, mRNA and protein expression of AR were elevated in E2-treated PCs cells. Cell proliferation rate was accelerated after 72h of E2 treatment, especially in AR-independent PC cells. In addition, the activity of AR was increased by E2 treatment, an effect that was reversed by specific ER-inhibitors (ICI-182780 and Tamoxifen). Intriguingly, an AR ligand-independent increase in psPSA-luc promoter activity was observed in response to E2 in ERα/β-transfected COS-7 cells. Treatment of COS-7 cells with MPP or ERα shRNA apparently decreased the promoter activity in ERα-transfected CO7 cells after E2 treatment. Conclusion: Taken together, estrogen-ERβ axis has a distinctive role in activating AR-signaling in prostate cancer cells. Importantly, high circulating levels of estrogens coupled with differential expression of ERβ in tumor cells suggest a potential role for estrogen-ERβ axis in development of castrate-resistant prostate cancer (CRPC) in AA men. Citation Format: Krzysztof Moroz, Zakaria Abd Elmageed, Sudesh Srivastav, Krishnarao Moparty, Krishnarao Moparty, Raju Thomas, Asim B. Abdel-Mageed. Estrogen-ERβ axis: Implications for racial disparity of prostate cancer. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B30.