Abstract SY09-02: Molecular mechanisms in prostate cancer in African Americans

Abstract

Abstract African American men have long been known to have the highest rates of prostate cancer (PCa) in the world. In addition, age adjusted mortality rates from PCa patients are two times worse among African Americans (AA) than Caucasians (CA). The reasons for the disparity in PCa risk, incidence, clinical progression, and disease-specific death are still controversial. In addition to socioeconomic and environmental factors, such as diet, access to care, and screenings, a biologically more aggressive cancer is proposed as one important explanation for the racial disparity observed in AA men. Androgens and the androgen receptor pathway are well established key regulators of aggressive PCa behavior. Using a novel proteomic pathway analysis comparing the distinct signal pathway and network proteins different between AA and CA PCa, we identified a number of markers including stem/progenitor cell and EMT related proteins that are overexpressed in PCa among AA. Our ongoing study indicates a novel link among Notch, WNT and androgen receptor (AR) pathways. In contrast to increase in epithelial AR, our data revealed a decrease in the expression of the stromal AR in AA PCa compared to CA PCa. Androgen and its receptor inhibit proliferation of prostate stromal cells through transcriptional suppression of cyclin B1. Mechanistically, the negative regulation of cyclin B1 by AR is mediated through switching between E2F1 and E2F4 on the promoter of cyclin B1. E2F1 binds to cyclin B1 promoter and maintains its expression and subsequent cell cycle progression in AR negative stromal cells or AR positive stromal cells under androgen depleted condition. Upon stimulation with androgen in AR positive stromal cells, E2F1 is displaced from the binding site by AR and replaced with E2F4, leading to recruitment of the SMRT/HDAC3 co-repressor complex and repression of cyclin B1. Furthermore, the switch between E2F1 and E2F4 at the E2F binding site of the cyclin B1 promoter coincides with an androgen-dependent interaction between AR and E2F1 as well as cytoplasm to nucleus translocation of E2F4. In summary, our study revealed an association between distinct epithelial and stromal AR expression and PCa racial disparity as well as the molecular mechanism involved in regulating AR expression in epithelial and stromal prostate cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY09-02. doi:1538-7445.AM2012-SY09-02