title: The androgen derivative 5alpha-androstane-3beta,17beta-diol inhibits prostate cancer cell migration through activation of the estrogen receptor beta 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 5alpha-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 5alpha-androstane-3beta,17beta-diol (3beta-Adiol), a steroid which does not bind androgen receptors, but efficiently binds the estrogen receptor beta (ERbeta), exerts a potent inhibition of prostate cancer cell migration through the activation of the ERbeta signaling. Very surprisingly, estradiol is not active, suggesting the existence of different pathways for ERbeta activation in prostate cancer cells. Moreover, 3beta-Adiol, through ERbeta, 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 3beta-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 (ERbeta-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 3beta-hydroxysteroid dehydrogenases (the enzymes responsible for 3beta-Adiol formation) are strongly correlated with hereditary prostate cancer.
authors.affiliation: Institute of Endocrinology, University of Milan, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Guerini
authors.forename: Daniela
authors.initials: D
authors.lastname: Sau
authors.forename: Eugenia
authors.initials: E
authors.lastname: Scaccianoce
authors.forename: Paola
authors.initials: P
authors.lastname: Rusmini
authors.forename: Paolo
authors.initials: P
authors.lastname: Ciana
authors.forename: Adriana
authors.initials: A
authors.lastname: Maggi
authors.forename: Paolo G V
authors.initials: PG
authors.lastname: Martini
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
authors.forename: Luciano
authors.initials: L
authors.lastname: Martini
authors.forename: Marcella
authors.initials: M
authors.lastname: Motta
authors.forename: Angelo
authors.initials: A
authors.lastname: Poletti
mesh_terms: D045930:Anabolic Agents / Q000494:pharmacology; D015113:Androstane-3,17-diol / Q000494:pharmacology*; D015820:Cadherins / Q000502:physiology; D045744:Cell Line, Tumor; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000187:drug effects*; D013196:Dihydrotestosterone / Q000378:metabolism / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000502:physiology*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D045930:Anabolic Agents; D015820:Cadherins; D047629:Estrogen Receptor beta; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D015113:Androstane-3,17-diol