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

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.