An J, Tzagarakis-Foster C, Scharschmidt T C, Lomri N, Leitman D C
Department of Obstetrics, Center for Reproductive Sciences, Gastroenterology Division and Liver Center, University of California, San Francisco, California 94143, USA.
J Biol Chem. 2001 May 25;276(21):17808-14. doi: 10.1074/jbc.M100953200. Epub 2001 Feb 21.
Estrogens used in hormone replacement therapy regimens may increase the risk of developing breast cancer. Paradoxically, high consumption of plant-derived phytoestrogens, particularly soybean isoflavones, is associated with a low incidence of breast cancer. To explore the molecular basis for these potential different clinical outcomes, we investigated whether soybean isoflavones elicit distinct transcriptional actions from estrogens. Our results demonstrate that the estrogen 17beta-estradiol effectively triggers the transcriptional activation and repression pathways with both estrogen receptors (ERs) ERalpha and ERbeta. In contrast, soybean isoflavones (genistein, daidzein, and biochanin A) are ERbeta-selective agonists of transcriptional repression and activation at physiological levels. The molecular mechanism for ERbeta selectivity by isoflavones involves their capacity to create an activation function-2 surface of ERbeta that has a greater affinity for coregulators than ERalpha. Phytoestrogens may act as natural selective estrogen receptor modulators that elicit distinct clinical effects from estrogens used for hormone replacement by selectively recruiting coregulatory proteins to ERbeta that trigger transcriptional pathways.
激素替代疗法中使用的雌激素可能会增加患乳腺癌的风险。矛盾的是，大量摄入植物源植物雌激素，尤其是大豆异黄酮，与乳腺癌的低发病率相关。为了探究这些潜在不同临床结果的分子基础，我们研究了大豆异黄酮是否会引发与雌激素不同的转录作用。我们的结果表明，雌激素17β-雌二醇能有效激活雌激素受体（ERs）ERα和ERβ的转录激活和抑制途径。相比之下，大豆异黄酮（染料木黄酮、大豆苷元和鹰嘴豆芽素A）在生理水平上是ERβ选择性转录抑制和激活激动剂。异黄酮对ERβ的选择性分子机制涉及其创造ERβ激活功能-2表面的能力，该表面对共调节因子的亲和力大于ERα。植物雌激素可能作为天然的选择性雌激素受体调节剂，通过选择性地将共调节蛋白招募到ERβ来触发转录途径，从而产生与用于激素替代的雌激素不同的临床效果。
