A MicroRNA196a2☆ and TP63 Circuit Regulated by Estrogen Receptor-α and ERK2 that Controls Breast Cancer Proliferation and Invasiveness Properties

Estrogen receptor alpha (ER alpha) is present in about 70 % of human breast cancers and, working in conjunction with extracellular signal-regulated kinase 2 (ERK2), this nuclear hormone receptor regulates the expression of many protein-encoding genes. Given the crucial roles of miRNAs in cancer biology, we investigated the regulation of miRNAs by estradiol (E2) through ER alpha and ERK2, and their impact on target gene expression and phenotypic properties of breast cancer cells. We identified miRNA-encoding genes harboring overlapping ER alpha and ERK chromatin binding sites in ER alpha-positive MCF-7 cells and showed ER alpha and ERK2 to bind to these sites and to be required for transcriptional induction of these miRNAs by E2. Hsa-miR-196a2*, the most highly estrogen up-regulated miRNA, markedly down-regulated tumor protein p63 (TP63), a member of the p53 family. In ER alpha-positive and ER alpha-negative breast cancer cells, proliferative and invasiveness properties were suppressed by hsa-miR-196a2* expression and enhanced by hsa-miR-196a2* antagonism or TP63 target protector oligonucleotides. Hsa-miR-196a2* and TP63 were inversely correlated in breast cancer cell lines and in a large cohort of human breast tumors, implying clinical relevance. The findings reveal a tumor suppressive role of hsa-miR-196a2* through regulation of TP63 by ER alpha and/or ERK2 signaling. Manipulating the hsa-miR-196a2*-TP63 axis might provide a potential tumor-suppressive strategy to alleviate the aggressive behavior and poor prognosis of some ER alpha-positive as well as many ER alpha-negative breast cancers.