The Evolving Role of Oestrogens and Their Receptors in the Development and Progression of Prostate Cancer

Context: Oestrogens were proven effective in the hormonal treatment of advanced prostate cancer (PCa) >60 yr ago and are still used as second-line hormonal therapy. Paradoxically, oestrogens might also be involved in the development and progression of PCa. Objective: To examine mechanisms of how oestrogens may affect prostate carcinogenesis and tumour progression. Evidence acquisition: Recent data obtained from animal, experimental, and clinical studies were reviewed. Evidence synthesis: The human prostate is equipped with a dual system of oestrogen receptors (oestrogen receptor alpha [ER alpha], oestrogen receptor beta [ER beta]) that undergoes profound remodelling during PCa development and tumour progression. in high-grade prostatic intraepithelial neoplasia (HGPIN), the ER alpha is upregulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models. Preliminary clinical studies with the ER alpha antagonist toremifene have identified the ER alpha as a promising target for PCa prevention. The partial loss of the ER beta in HGPIN indicates that the ER beta acts as a tumour suppressor. The ER beta is generally retained in hormone-naive PCa but is partially lost in castration-resistant disease. The progressive emergence of the ER alpha and the oestrogen-regulated progesterone receptor (PR) during PCa progression and hormone-refractory disease suggests that these tumours can use oestrogens and progestins for their growth. The TMPRSS2-ERG gene fusion recently reported as a potentially aggressive molecular subtype of PCa is regulated by ER-dependent signalling. TMPRSS2-ERG expression has been found to be increased by ER alpha agonist (oestrogens) and decreased by ER beta agonists. Conclusions: Oestrogens and their receptors are implicated in PCa development and tumour progression. There is significant potential for the use of ER alpha antagonists and ER beta agonists to prevent PCa and delay disease progression. Tumours equipped with the pertinent receptors are potential candidates for this new therapeutic approach. (C) 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.