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