Platinum Priority – Review – Prostate CancerEditorial by Alberto Briganti on pp. 543–545 of this issueThe Evolving Role of Oestrogens and Their Receptors in the Development and Progression of Prostate Cancer☆
Introduction
The androgen receptor (AR) is the major target for prostate cancer (PCa) prevention and treatment. Nevertheless, there is a growing body of evidence to suggest that oestrogen signalling also plays a significant role in normal and abnormal growth of the prostate gland [1], [2], [3], [4]. Oestrogen action in the male must be viewed in at least two different ways: (1) systemic endocrine effects acting through the pituitary gland to indirectly lower androgens, and (2) local effects that directly target prostate tissue by specific oestrogen receptors (ER). The human prostate is equipped with a dual system of ERs (oestrogen receptor alpha [ERα] and oestrogen receptor beta [ERβ]) that undergoes profound remodelling during PCa development and tumour progression [5], [6], [7]. In the normal prostate, the ERα is restricted to stromal cells and to the androgen-independent basal cell layer, which harbours prostate stem cells and the proliferation compartment of the prostate epithelium [5], [8]. ERβ is predominately expressed in luminal cells, which are androgen dependent but have a limited proliferation capacity [7], [8].
Section snippets
Role of oestrogens and their receptors in prostatic carcinogenesis
Oestrogens (estradiol) exert carcinogenic effects on the prostatic epithelium. This knowledge is derived from experimental data reported in animal models (recently reviewed by Bosland [9]). Briefly, when testosterone is chronically administered to Noble rats at low doses, PCa develops through high-grade prostatic intraepithelial neoplasia (HGPIN) in 35–40% of cases. When estradiol is given together with low-dose testosterone, the incidence of prostate carcinomas increases to nearly 100%. This
Preclinical studies with selective oestrogen receptor modulators
Several selective ER modulators (SERM) have been tested in preclinical studies (recently reviewed by Bosland [9]). Briefly, tamoxifen inhibits proliferation of PC-3 and DU-145 PCa cells and induces apoptosis in LNCaP cells. Tamoxifen also inhibits in vivo growth of the CWR22 PCa xenograft in nude mice. Raloxifene (a mixed oestrogen agonist/antagonist) induces apoptosis in LNCaP cells. Both raloxifene and the ERα antagonist trioxifene reduce the development of pulmonary metastasis and extend
Conclusions
Although the AR remains the major target for PCa prevention and treatment, there are multiple lines of evidence to suggest that oestrogens and their receptors (ERα, ERβ) are also involved in PCa development and tumour progression. This is particularly evident in prostate carcinogenesis, where ERα signalling potentiates the carcinogenic effects of androgens on the prostatic epithelium. Based on the promising nature of the phase 2b trial outcome with the ERα antagonist toremifene, a phase 3 trial
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