miR-18a activates Wnt pathway in ER-positive breast cancer and is associated with poor prognosis

Despite the established benefits of long-term endocrine therapy, women with hormone receptor-positive breast cancer remain at risk for late relapse. The basis of this is multi-factorial including genetic, epigenetic, and host factors. In this study we have explored the epigenetic regulation of estrogen receptor (ER)-dependent molecular and cellular phenotype by hsa-miR-18a-5p using well-established human ER-positive (ER+) breast cancer cell lines. miR-18a was overexpressed in MCF7 and ZR-75-1 and this led to an increase in the proliferative ability of the cells and concurrently resulted in decreased expression of luminal markers and higher expression of the basal marker, cytokeratin 14. The cells became more migratory with a significant repression of E-cadherin and activation of the Wnt noncanonical pathway. We observed an activation of the planar cell polarity (PCP) pathway with increased activation of JNK pathway and eventually change in actin dynamics. There was increased F-actin polymerization in cells with higher expression of miR-18a. Examination of miR-18a expression in a set of human ER+ breast cancer specimens showed a negative correlation between miR-18a andESR1transcripts as well as ER protein. Kaplan-Meier survival analysis of the cohort stratified by tumor hsa-miR-18a-5p levels produced significant differences in disease-free survival (log rankP < .05). This observation was independently validated in the METABRIC cohort. These data provide support for a role of hsa-miR-18a-5p in altering the proliferative and migratory behavior of ER+ cells and its potential utility as a prognostic marker in clinical ER+ breast cancers.