Prostate cancer is a leading cause of cancer death in American males. The major medical therapy for metastasized prostate cancer includes various regimens of androgen ablation. Androgens especially dihydrotestosterone (DHT) play a critical role in prostate development, growth and pathogenesis of benign prostate hyperplasia and prostate cancer. In the prostate, the action of androgen can be modulated by estrogen. Both androgens and estrogens display their action via their corresponding androgen receptor (AR) and estrogen receptors (ERs), respectively. Currently, one AR and two ERs, ERalpha and ERbeta, have been identified. The two ERs may possess differential effects in mediating estrogen actions. In pilot studies, we have found that DHT was the major androgen to induce prostate growth and prostate specific antigen gene expression. Interestingly, DHT action was modulated by estrogen in a receptor-isoform and ligand specific manner. 17alpha-estradiol was anti-androgenic and anti-growth in prostate tumor cells. Thus, we'll further explore in greater detail the effects of estrogen analogs on the modulation of DHT actions and prostatic tumor cell growth using in vitro and in vivo models to test the hypothesis that the effects of estrogens are ER-isofrom and ER-ligand specific, and 17alpha-estradiol is a potential agent for prostate cancer therapy. The ER-isoform specificity of estrogen action on modulating DHT-induced PSA gene expression will be determined in prostatic tumor LAPC-4 cells, and the effects of different ER-ligands compared. The ERisoform specificity will be further analyzed in ERalpha and ERbeta knockout animals, and in prostatic tumor LAPC-4 cells using antisense technology. By comparing the effects of various ER-ligands on regulating prostate cancer cell growth and proliferation in cell culture and in animal models, the ligand specificity of estrogen action will be determined. The anti-androgenic and antitumor effects of 17alpha-estradiol will be further explored in cell culture and in a xenograft animal model of prostate cancer. Elucidation of receptor-isoform and ligand specificity of estrogen-androgen interaction will facilitate our understanding of sex-steroid interaction in prostate physiology and pathogenesis, and the development of specific ER-ligands for the treatment of androgen-dependent and androgen-independent prostate cancer.
