Estrogen receptor beta and the progression of prostate cancer: role of 5alpha-androstane-3beta,17beta-diol.
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.
Dondi
Donatella
D
Departments of Endocrinology, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy.
Piccolella
Margherita
M
Biserni
Andrea
A
Della Torre
Sara
S
Ramachandran
Balaji
B
Locatelli
Alessia
A
Rusmini
Paola
P
Sau
Daniela
D
Caruso
Donatella
D
Maggi
Adriana
A
Ciana
Paolo
P
Poletti
Angelo
A
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
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