Endocrinology, 2012, 153(9):4160-70.

Aggressive Prostate Cancer Is Prevented in ERαKO Mice and Stimulated in ERβKO TRAMP Mice

Anna Slusarz, Glenn A Jackson, J. Kevin Day, et al

Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, USA; et al

Previous evidence suggests soy genistein may be protective against prostate cancer, but whether this protection involves an estrogen receptor (ER)-dependent mechanism is unknown. To test the hypothesis that phytoestrogens may act through ERα or ERβ to play a protective role against prostate cancer, we bred transgenic mice lacking functional ERα or ERβ with transgenic adenocarcinoma of mouse prostate (TRAMP) mice. Dietary genistein reduced the incidence of cancer in ER wild-type (WT)/transgenic adenocarcinoma of mouse prostate mice but not in ERα knockout (KO) or ERβKO mice. Cancer incidence was 70% in ERWT mice fed the control diet compared with 47% in ERWT mice fed low-dose genistein (300 mg/kg) and 32% on the high-dose genistein (750 mg/kg). Surprisingly, genistein only affected the well differentiated carcinoma (WDC) incidence but had no effect on poorly differentiated carcinoma (PDC). No dietary effects have been observed in either of the ERKO animals. We observed a very strong genotypic influence on PDC incidence, a protective effect in ERαKO (only 5% developed PDC), compared with 19% in the ERWT, and an increase in the incidence of PDC in ERβKO mice to 41%. Interestingly, immunohistochemical analysis showed ERα expression changing from nonnuclear in WDC to nuclear in PDC, with little change in ERβ location or expression. In conclusion, genistein is able to inhibit WDC in the presence of both ERs, but the effect of estrogen signaling on PDC is dominant over any dietary treatment, suggesting that improved differential targeting of ERα vs. ERβ would result in prevention of advanced prostate cancer.

英国《内分泌学》，2012年9月

在 ERαKO 小鼠中侵略性前列腺癌被阻止而在 ERβKO 小鼠中被激发

安娜 思路塞斯，格伦 A 杰克逊，J 凯文 戴，等

美国密苏里大学化学学院等

以前的证据表明，大豆金雀异黄素可以预防前列腺癌，但这种保护是否涉及到雌激素受体 (ER)-依赖的机制尚不清楚。为了验证植物雌激素可以通过 ERα 或 ERβ 发挥对前列腺癌的保护作用的假设，我们培育了缺失功能性 ERα 或 ERβ 但具有小鼠前列腺 （TRAMP）癌转基因的小鼠。膳食金雀异黄素降低了ER 野生型 (WT) / 转基因前列腺癌小鼠的癌症发病率，但没有降低ERα 基因敲除(KO) 或 ERβKO 小鼠腺癌的发病率。用空白对照饮食喂养的ERWT小鼠癌症发生率为 70 %，而用低剂量 （300 mg/kg） 和高剂量（750 mg/kg）金雀异黄素喂养的ERWT小鼠癌症发生率分别为47 %和32%。出人意料的是，金雀异黄素只影响高分化的肿瘤 (WDC) 发生率但不影响低分化的肿瘤 (PDC)。在ERKO动物之中，没有发现饮食的影响。我们观察到对 PDC 发病率很强的基因型影响，在 ERαKO 的一种保护作用（仅 5%已开发的 PDC），相比，ERWT的19%， 在ERβKO 小鼠中PDC的发病率增加到 41%。有趣的是，免疫组织化学分析表明ERα 的表达从WDC的无核 改变成PDC的有核，伴随着与 ERβ 定位或表达的小变化。总结，金雀异黄素在两种ER存在的情况下能够抑制 WDC ，但是雌激素信号对 PDC的影响在饮食治疗中占主导地位，这表明，改进的微分靶向性ERα 与 ERβ可以预防晚期前列腺癌。