MiR-137 Targets Estrogen-Related Receptor Alpha and Impairs the Proliferative and Migratory Capacity of Breast Cancer Cells

ERR alpha is an orphan nuclear receptor emerging as a novel biomarker of breast cancer. Over-expression of ERR alpha in breast tumor is considered as a prognostic factor of poor clinical outcome. The mechanisms underlying the dysexpression of this nuclear receptor, however, are poorly understood. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level and play important roles in tumor initiation and progression. In the present study, we have identified that the expression of ERR alpha is regulated by miR-137, a potential tumor suppressor microRNA. The bioinformatics search revealed two putative and highly conserved target-sites for miR-137 located within the ERR alpha 3'UTR at nt 480-486 and nt 596-602 respectively. Luciferase-reporter assay demonstrated that the two predicted target sites were authentically functional. They mediated the repression of reporter gene expression induced by miR-137 in an additive manner. Moreover, ectopic expression of miR-137 down-regulated ERR alpha expression at both protein level and mRNA level, and the miR-137 induced ERR alpha-knockdown contributed to the impaired proliferative and migratory capacity of breast cancer cells. Furthermore, transfection with miR-137mimics suppressed at least two downstream target genes of ERR alpha-CCNE1 and WNT11, which are important effectors of ERR alpha implicated in tumor proliferation and migration. Taken together, our results establish a role of miR-137 in negatively regulating ERR alpha expression and breast cancer cell proliferation and migration. They suggest that manipulating the expression level of ERR alpha by microRNAs has the potential to influence breast cancer progression.