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J. Biol. Chem., Vol. 283, Issue 45, 31079-31086, November 7, 2008

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MicroRNA-221/222 Negatively Regulates Estrogen Receptor and Is Associated with Tamoxifen Resistance in Breast Cancer^*

Jian-Jun Zhao¹, Jianhong Lin¹, Hua Yang, William Kong, Lili He, Xu Ma, Domenico Coppola, and Jin Q. Cheng²

From the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612 and the National Research Institute for Family Planning, Peking Union Medical College, Tsinghua University, Beijing 100081, China

A search for regulators of estrogen receptor (ER) expression has yielded a set of microRNAs (miRNAs) for which expression is specifically elevated in ER-negative breast cancer. Here we show distinct expression of a panel of miRNAs between ER-positive and ER-negative breast cancer cell lines and primary tumors. Of the elevated miRNAs in ER-negative cells, miR-221 and miR-222 directly interact with the 3'-untranslated region of ER. Ectopic expression of miR-221 and miR-222 in MCF-7 and T47D cells resulted in a decrease in expression of ER protein but not mRNA, whereas knockdown of miR-221 and miR-222 partially restored ER in ER 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 expression at the protein level and could be potential targets for restoring ER expression and responding to antiestrogen therapy in a subset of breast cancers.

Received for publication, August 5, 2008 , and in revised form, September 10, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants CA77935 and CA107078. This work was also supported by United States Department of Defense Grant DAMD17-02-1-0671 and BankheadColey Grant 07BB-01. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: H. Lee Moffitt Cancer Center and Research Inst., 12902 Magnolia Dr., SRB3, Tampa, FL 33612. Tel.: 813-745-6915; Fax: 813-745-3829; E-mail: jin.cheng{at}moffitt.org.

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