Bonkhoff Helmut, Berges Richard
Pathology Laboratories, Tietzenweg 129, 12203 Berlin, Germany.
Eur Urol. 2009 Mar;55(3):533-42. doi: 10.1016/j.eururo.2008.10.035. Epub 2008 Nov 6.
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.
To examine mechanisms of how oestrogens may affect prostate carcinogenesis and tumour progression.
Recent data obtained from animal, experimental, and clinical studies were reviewed.
The human prostate is equipped with a dual system of oestrogen receptors (oestrogen receptor alpha [ERalpha], oestrogen receptor beta [ERbeta]) that undergoes profound remodelling during PCa development and tumour progression. In high-grade prostatic intraepithelial neoplasia (HGPIN), the ERalpha is upregulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models. Preliminary clinical studies with the ERalpha antagonist toremifene have identified the ERalpha as a promising target for PCa prevention. The partial loss of the ERbeta in HGPIN indicates that the ERbeta acts as a tumour suppressor. The ERbeta is generally retained in hormone-naïve PCa but is partially lost in castration-resistant disease. The progressive emergence of the ERalpha 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 ERalpha agonist (oestrogens) and decreased by ERbeta agonists.
Oestrogens and their receptors are implicated in PCa development and tumour progression. There is significant potential for the use of ERalpha antagonists and ERbeta agonists to prevent PCa and delay disease progression. Tumours equipped with the pertinent receptors are potential candidates for this new therapeutic approach.
60多年前已证实雌激素在晚期前列腺癌（PCa）的激素治疗中有效，目前仍用作二线激素疗法。矛盾的是，雌激素也可能参与PCa的发生和进展。
研究雌激素影响前列腺癌发生和肿瘤进展的机制。
回顾了近期从动物、实验和临床研究中获得的数据。
人类前列腺具有双重雌激素受体系统（雌激素受体α[ERα]、雌激素受体β[ERβ]），在PCa发生和肿瘤进展过程中会经历深刻重塑。在高级别前列腺上皮内瘤变（HGPIN）中，ERα上调，在动物模型中已证实其最有可能介导雌二醇的致癌作用。使用ERα拮抗剂托瑞米芬的初步临床研究已确定ERα是预防PCa的一个有前景的靶点。HGPIN中ERβ部分缺失表明ERβ起肿瘤抑制作用。ERβ通常在未经激素治疗的PCa中保留，但在去势抵抗性疾病中部分丧失。在PCa进展和激素难治性疾病过程中，ERα和雌激素调节的孕激素受体（PR）逐渐出现，提示这些肿瘤可利用雌激素和孕激素促进生长。最近报道的TMPRSS2-ERG基因融合是PCa一种潜在侵袭性分子亚型，受雌激素依赖性信号调控。已发现ERα激动剂（雌激素）可增加TMPRSS2-ERG表达，而ERβ激动剂则使其降低。
雌激素及其受体与PCa发生和肿瘤进展有关。使用ERα拮抗剂和ERβ激动剂预防PCa和延缓疾病进展具有很大潜力。配备相关受体的肿瘤是这种新治疗方法的潜在候选对象。
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