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

• Published in: The Journal of biological chemistry Vol. 283; no. 45; pp. 31079 - 31087
• Main Authors: Zhao, Jian-Jun, Lin, Jianhong, Yang, Hua, Kong, William, He, Lili, Ma, Xu, Coppola, Domenico, Cheng, Jin Q.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07-11-2008; American Society for Biochemistry and Molecular Biology
• Subjects: 3' Untranslated Regions - genetics; 3' Untranslated Regions - metabolism; Antineoplastic Agents, Hormonal - pharmacology; Apoptosis - drug effects; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cell Line, Tumor; Drug Resistance, Neoplasm - drug effects; Estrogen Receptor alpha - biosynthesis; Estrogen Receptor alpha - genetics; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; MicroRNAs - genetics; MicroRNAs - metabolism; Molecular Basis of Cell and Developmental Biology; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; RNA, Neoplasm - genetics; RNA, Neoplasm - metabolism; Tamoxifen - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M806041200

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