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In earlier stages, prostate cancer (PC) depends on androgens and may be reduced with androgen blockade. Androgen-ablation therapy often induces androgen-independent PC, characterized by an increased invasiveness. We have found that the the testosterone derivative, dihydrotestosterone inhibits cell migration with an androgen receptor (AR)-independent mechanism. This effect has been linked to its metabolite 5alpha-androstane-3beta,17beta-diol (3beta-Adiol), a steroid which does not bind AR, but interact with the estrogen receptor beta (ERbeta). 3beta-Adiol inhibits cell migration of PC through the activation of the ERbeta signalling, while estradiol is not active, suggesting the existence of different pathways for ERbeta activation in PC cells. Moreover, 3beta-Adiol induces the expression of E-cadherin, a protein known to be capable to reduce metastasis formation of breast cancer and PC cells. The inhibitory effects of 3beta-Adiol on PC cell migration is counteracted by siRNA against E-cadherin. The present data demonstrated that 1) testosterone may exert an estrogenic effects downstream in the catabolic process present in the prostate; 2) the estrogenic effect of testosterone derivatives (ERbeta-dependent) inhihits cell migration, although it is apparently different from that linked to estradiol on the same receptor and may be protective against PC invasion and metastasis. These results may help to explain some clinical observations which reported that alterations in gene coding for 3beta-HSDs (the enzymes responsible for 3beta-Adiol formation) are strongly correlated with hereditary PC.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]