The androgen derivative 5α-androstane-3β,17β-diol inhibits prostate cancer cell migration through activation of the estrogen receptor β subtype

Abstract

Prostate cancer growth depends, in its earlier stages, on androgens and is usually pharmacologically modulated with androgen blockade. However, androgen-ablation therapy may generate androgen-independent prostate cancer, often characterized by an increased invasiveness. We have found that the 5α-reduced testosterone derivative, dihydrotestosterone (the most potent natural androgen) inhibits cell migration with an androgen receptor-independent mechanism. We have shown that the dihydrotestosterone metabolite 5α-androstane-3β,17β-diol (3β-Adiol), a steroid which does not bind androgen receptors, but efficiently binds the estrogen receptor β (ERβ), exerts a potent inhibition of prostate cancer cell migration through the activation of the ERβ signaling. Very surprisingly, estradiol is not active, suggesting the existence of different pathways for ERβ activation in prostate cancer cells. Moreover, 3β-Adiol, through ERβ, induces the expression of E-cadherin, a protein known to be capable of blocking metastasis formation in breast and prostate cancer cells. The inhibitory effects of 3β-Adiol on prostate cancer cell migration is counteracted by short interfering RNA against E-cadherin. Altogether, the data showed that (a) circulating testosterone may act with estrogenic effects downstream in the catabolic process present in the prostate, and (b) that the estrogenic effect of testosterone derivatives (ERβ-dependent) results in the inhibition of cell migration, although it is apparently different from that linked to estradiol on the same receptor and may be protective against prostate cancer invasion and metastasis. These results also shed some light on clinical observations suggesting that alterations in genes coding for 3β-hydroxysteroid dehydrogenases (the enzymes responsible for 3β-Adiol formation) are strongly correlated with hereditary prostate cancer. © 2005 American Association for Cancer Research.