Differential effects of estrogen receptor ligands on regulation of dihydrotestosterone-induced cell proliferation in endothelial and prostate cancer cells.

Androgen deprivation therapy of prostate cancer with estrogens shows significant cardiovascular side-effects. To develop effective prostate cancer therapeutic agent(s) with minimal cardiovascular side-effects, we compared the effects of various estrogen receptor (ER) ligands on the modulation of dihydrotestosterone (DHT) actions in LAPC-4 and LNCaP prostate cancer cells and human aortic endothelial cells (HAECs). DHT stimulated the proliferation of HAEC, LAPC-4 and LNCaP cells and induced PSA mRNA expression in LAPC-4 cells. These DHT actions were differentially modulated by ER ligands in a cell-dependent manner. In LAPC-4 cells, knockdown of ERβ expression partially eliminated the βE2 inhibition of DHT-induced LAPC-4 cell proliferation, and a parallel change was observed between ER ligand modulation of DHT-induced cell proliferation and cyclin A expression. The obtained data suggest that it is feasible to develop effective agent(s) for prostate cancer therapy with minimal cardiovascular side-effects and 17α-estradiol and genistein are such potential agents.