MicroRNA-221/222 Negatively Regulates Estrogen Receptor α and Is Associated with Tamoxifen Resistance in Breast Cancer (Retracted Article)
MicroRNA-221/222 Negatively Regulates Estrogen Receptor α and Is Associated with Tamoxifen Resistance in Breast Cancer (Retracted Article)
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DOI：
10.1074/jbc.m806041200
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发表时间：
2008-11-07
影响因子：
4.8
通讯作者：
Cheng, Jin Q.
中科院分区：
文献类型：
--
作者：
Zhao, Jian-Jun;Lin, Jianhong;Cheng, Jin Q.
对雌激素受体α（ER α）表达调节因子的研究已经产生了一组microRNA（miRNA），其表达在ER α阴性乳腺癌中特异性升高。在这里，我们展示了ER α阳性和ER α阴性乳腺癌细胞系和原发性肿瘤之间一组miRNA的不同表达。在ER α阴性细胞中升高的miRNA中，miR-221和miR-222直接与ER α的3 '-非翻译区相互作用。miR-221和miR-222在MCF-7和T47 D细胞中的异位表达导致ER α蛋白表达的降低，而不是mRNA表达的降低，而miR-221和miR-222的敲低部分恢复了ER α蛋白阴性/mRNA阳性细胞中的ER α。值得注意的是，与载体处理的细胞相比，miR-221和/或miR-222转染的MCF-7和T47 D细胞变得对他莫昔芬耐药。此外，miR-221和/或miR-222的敲低使MDA-MB-468细胞对他莫昔芬诱导的细胞生长停滞和凋亡敏感。这些发现表明，miR-221和miR-222在蛋白质水平上对ER α表达的调节中起着重要作用，并且可能是恢复ER α表达和对乳腺癌亚组中的抗雌激素治疗作出反应的潜在靶点。
A search for regulators of estrogen receptor alpha(ER alpha) expression has yielded a set of microRNAs (miRNAs) for which expression is specifically elevated in ER alpha-negative breast cancer. Here we show distinct expression of a panel of miRNAs between ER alpha-positive and ER alpha-negative breast cancer cell lines and primary tumors. Of the elevated miRNAs in ER alpha-negative cells, miR-221 and miR-222 directly interact with the 3'-untranslated region of ER alpha. Ectopic expression of miR-221 and miR-222 in MCF-7 and T47D cells resulted in a decrease in expression of ER alpha protein but not mRNA, whereas knockdown of miR-221 and miR-222 partially restored ER alpha in ER alpha protein-negative/mRNA-positive cells. Notably, miR-221- and/or miR-222-transfected MCF-7 and T47D cells became resistant to tamoxifen compared with vector-treated cells. Furthermore, knockdown of miR-221 and/or miR-222 sensitized MDA-MB-468 cells to tamoxifen-induced cell growth arrest and apoptosis. These findings indicate that miR-221 and miR-222 play a significant role in the regulation of ER alpha expression at the protein level and could be potential targets for restoring ER alpha expression and responding to antiestrogen therapy in a subset of breast cancers.