Molecular determinants for the tissue specificity of SERMs
Molecular determinants for the tissue specificity of SERMs
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DOI：
10.1126/science.1068537
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发表时间：
2002-03-29
期刊：
影响因子：
56.9
通讯作者：
Brown, M
中科院分区：
文献类型：
--
作者：
Shang, YF;Brown, M
选择性雌激素受体调节剂(SERM)在某些组织中模仿雌激素的作用，而在其他组织中则相反。他莫昔芬和雷洛昔芬等SERMS对乳腺癌的疗效取决于它们的抗雌激素活性。然而，在子宫中，他莫昔芬是雌激素。在这里，我们证明了他莫昔芬和雷洛昔芬都能在乳腺细胞中诱导辅阻遏子向靶基因启动子募集。在子宫内膜细胞中，他莫昔芬，而不是雷洛昔芬，通过刺激辅助激活因子向基因的子集募集，起到了雌激素的作用。他莫昔芬在子宫中的雌激素样活性需要高水平的类固醇受体辅活化子1(SRC-1)的表达。因此，辅调节因子募集中细胞类型和启动子特异性的差异决定了细胞对SERM的反应。
Selective estrogen receptor modulators (SERMs) mimic estrogen action in certain tissues while opposing it in others. The therapeutic effectiveness of SERMS such as tamoxifen and raloxifene in breast cancer depends on their antiestrogenic activity. In the uterus, however, tamoxifen is estrogenic. Here, we show that both tamoxifen and raloxifene induce the recruitment of corepressors to target gene promoters in mammary cells. In endometrial cells, tamoxifen, but not raloxifene, acts like estrogen by stimulating the recruitment of coactivators to a subset of genes. The estrogen-like activity of tamoxifen in the uterus requires a high level of steroid receptor coactivator 1 (SRC-1) expression. Thus cell type- and promoter-specific differences in coregulator recruitment determine the cellular response to SERMs.