Mechanisms enforcing the estrogen receptor β selectivity of botanical estrogens
Mechanisms enforcing the estrogen receptor β selectivity of botanical estrogens
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DOI：
10.1096/fj.13-234617
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发表时间：
2013-11-01
期刊：
影响因子：
4.8
通讯作者：
Katzenellenbogen, Benita S.
中科院分区：
文献类型：
--
作者：
Jiang, Yan;Gong, Ping;Katzenellenbogen, Benita S.
由于对绝经期妇女广泛消耗的植物雌激素(BES)的作用知之甚少，我们研究了一些主要的BES的机制和细胞活性。我们研究了染料木素、大豆苷元、木马素和甘草素与雌激素受体ER和ER、与关键辅助调节因子(SRC3和RIP140)和染色质结合部位的相互作用，以及在含有ER和/或ER的MCF-7乳腺癌细胞中对基因表达和增殖的调控。与内源性雌激素不同，雌二醇(E2)优先与ER结合，但其在基因刺激中的ER效力选择性(340-830倍于E2)在多个水平上得到增强(辅助调节因子招募、染色质结合)；然而，在较高浓度(0.1或1M)时，BES也完全激活ER。由于ER促进乳腺癌细胞增殖，而ER抑制这一过程，靶细胞中这两种ER的相对水平和BE剂量极大地影响基因表达和增殖反应，并将成为BES潜在益处与风险的关键决定因素。我们的发现揭示了BES和E2在雌激素活性方面的关键和新的机制差异，BES显示的活动模式与E2明显不同，并为未来的研究提供了有价值的信息。
Because little is known about the actions of botanical estrogens (BEs), widely consumed by menopausal women, we investigated the mechanistic and cellular activities of some major BEs. We examined the interactions of genistein, daidzein, equol, and liquiritigenin with estrogen receptors ER and ER, with key coregulators (SRC3 and RIP140) and chromatin binding sites, and the regulation of gene expression and proliferation in MCF-7 breast cancer cells containing ER and/or ER. Unlike the endogenous estrogen, estradiol (E2), BEs preferentially bind to ER, but their ER-potency selectivity in gene stimulation (340- to 830-fold vs. E2) is enhanced at several levels (coregulator recruitment, chromatin binding); nevertheless, at high (0.1 or 1 M) concentrations, BEs also fully activate ER. Because ER drives breast cancer cell proliferation and ER dampens this, the relative levels of these two ERs in target cells and the BE dose greatly affect gene expression and proliferative response and will be crucial determinants of the potential benefits vs. risks of BEs. Our findings reveal key and novel mechanistic differences in the estrogenic activities of BEs vs. E2, with BEs displaying patterns of activity distinctly different from those seen with E2 and provide valuable information to inform future studies.Jiang, Y., Gong, P., Madak-Erdogan, Z., Martin, T., Jeyakumar, M., Carlson, K., Khan, I., Smillie, T. J., Chittiboyina, A. G., Rotte, S. C. K., Helferich, W. G., Katzenellenbogen, J. A., Katzenellenbogen, B. S. Mechanisms enforcing the estrogen receptor selectivity of botanical estrogens.