Prostate cancer (PC) develops in response to an abnormal activation of androgen receptor induced by circulating androgens and, in its initial stages, is pharmacologically controlled by androgen blockade. However, androgen ablation therapy often allows androgen-independent PC development, generally characterized by increased invasiveness. We previously reported that 5α-androstane-3β,17β-diol (3β-Adiol) inhibits the migration of PC cell lines via the estrogen receptor β (ERβ) activation. Here, by combining in vitro assays and in vivo imaging approaches, we analyzed the effects of 3β-Adiol on PC proliferation, migration, invasiveness, and metastasis in cultured cells and in xenografts using luciferase-labeled PC3 (PC3-Luc) cells. We found that 3β-Adiol not only inhibits PC3-Luc cell migratory properties, but also induces a broader anti-tumor phenotype by decreasing the proliferation rate, increasing cell adhesion, and reducing invasive capabilities in vitro. All these 3β-Adiol activities are mediated by ERβ and cannot be reproduced by the physiological estrogen, 17β-estradiol, suggesting the existence of different pathways activated by the two ERβ ligands in PC3-Luc cells. In vivo, continuous administration of 3β-Adiol reduces growth of established tumors and counteracts metastasis formation when PC3-Luc cells are engrafted s.c. in nude mice or are orthotopically injected into the prostate. Since 3β-Adiol has no androgenic activity, and cannot be converted to androgenic compounds, the effects here described entail a novel potential application of this agent against human PC.
Estrogen receptor β and the progression of prostate cancer: role of 5α-androstane-3β,17β-diol
