MicroRNA-497 downregulation contributes to cell proliferation, migration, and invasion of estrogen receptor alpha negative breast cancer by targeting estrogen-related receptor alpha

Metastasis has become the main challenge for treatment of estrogen receptor alpha (ER alpha) negative breast cancer. Here, we found a negative correlation between miR-497 and estrogen-related receptor alpha (ERR alpha), a nuclear receptor overexpressed in ER alpha negative breast cancer. Targeted inhibition of ERR alpha by si-RNA increased miR-497 expression while overexpression of ERR alpha inhibited miR-497 expression. Further investigation showed that miR-497 targeted ERR alpha by binding to the 3'UTR region of ERR alpha. Luciferase assay and ChIP assay confirmed that ER alpha directly regulated the transcription of miR-497, suggesting that loss of ER alpha lowered miR-497 level in ER alpha negative breast cancer. Further, overexpression of miR-497 not only inhibited ERR alpha expression but also reduced MIF level and MMP9 activity, which led to significant decreases in cell proliferation, migration, and invasion of ER alpha negative breast cancer. Taken together, our findings suggested that, in ER alpha negative breast cancer, the low level of ER alpha reduced miR-497 expression, which promoted ERR alpha expression that enhanced cell proliferation, migration, and invasion by increasing MIF expression and MMP9 activity.