Elsevier

European Urology

Volume 55, Issue 3, March 2009, Pages 533-542
European Urology

Platinum Priority – Review – Prostate Cancer
Editorial by Alberto Briganti on pp. 543–545 of this issue
The Evolving Role of Oestrogens and Their Receptors in the Development and Progression of Prostate Cancer

https://doi.org/10.1016/j.eururo.2008.10.035Get rights and content

Abstract

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 [ERα], oestrogen receptor beta [ERβ]) that undergoes profound remodelling during PCa development and tumour progression. In high-grade prostatic intraepithelial neoplasia (HGPIN), the ERα is upregulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models. Preliminary clinical studies with the ERα antagonist toremifene have identified the ERα as a promising target for PCa prevention. The partial loss of the ERβ in HGPIN indicates that the ERβ acts as a tumour suppressor. The ERβ is generally retained in hormone-naïve PCa but is partially lost in castration-resistant disease. The progressive emergence of the ERα 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 ERα agonist (oestrogens) and decreased by ERβ agonists.

Conclusions

Oestrogens and their receptors are implicated in PCa development and tumour progression. There is significant potential for the use of ERα antagonists and ERβ agonists to prevent PCa and delay disease progression. Tumours equipped with the pertinent receptors are potential candidates for this new therapeutic approach.

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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