title: Estrogen receptor beta and the progression of prostate cancer: role of 5alpha-androstane-3beta,17beta-diol.
abstract: 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 5alpha-androstane-3beta,17beta-diol (3beta-Adiol) inhibits the migration of PC cell lines via the estrogen receptor beta (ERbeta) activation. Here, by combining in vitro assays and in vivo imaging approaches, we analyzed the effects of 3beta-Adiol on PC proliferation, migration, invasiveness, and metastasis in cultured cells and in xenografts using luciferase-labeled PC3 (PC3-Luc) cells. We found that 3beta-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 3beta-Adiol activities are mediated by ERbeta and cannot be reproduced by the physiological estrogen, 17beta-estradiol, suggesting the existence of different pathways activated by the two ERbeta ligands in PC3-Luc cells. In vivo, continuous administration of 3beta-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 3beta-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.
authors.affiliation: Departments of Endocrinology, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Dondi
authors.forename: Margherita
authors.initials: M
authors.lastname: Piccolella
authors.forename: Andrea
authors.initials: A
authors.lastname: Biserni
authors.forename: Sara
authors.initials: S
authors.lastname: Della Torre
authors.forename: Balaji
authors.initials: B
authors.lastname: Ramachandran
authors.forename: Alessia
authors.initials: A
authors.lastname: Locatelli
authors.forename: Paola
authors.initials: P
authors.lastname: Rusmini
authors.forename: Daniela
authors.initials: D
authors.lastname: Sau
authors.forename: Donatella
authors.initials: D
authors.lastname: Caruso
authors.forename: Adriana
authors.initials: A
authors.lastname: Maggi
authors.forename: Paolo
authors.initials: P
authors.lastname: Ciana
authors.forename: Angelo
authors.initials: A
authors.lastname: Poletti
mesh_terms: D045930:Anabolic Agents / Q000494:pharmacology*; D015113:Androstane-3,17-diol / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D047629:Estrogen Receptor beta / Q000378:metabolism*; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D011509:Proteoglycans / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
chemical_list: D045930:Anabolic Agents; D004338:Drug Combinations; D047629:Estrogen Receptor beta; D007797:Laminin; D011509:Proteoglycans; D011944:Receptors, Androgen; C059485:matrigel; D015113:Androstane-3,17-diol; D003094:Collagen