microRNA 146a suppresses tumor progression and enhances therapeutic sensitivity by targeting the EGFR pathway in BRCA1-associated basal-like breast cancers

BRCA1-associated basal-like breast cancers (BLBCs) are high-grade ductal carcinomas that frequently overexpress epidermal growth factor receptor (EGFR). EGFR overexpression is associated with tumor progression and metastasis, resistance to radiation and chemotherapy, and poor prognosis. Though EGFR inhibitors have been used to treat other cancers, clinical trials for breast cancer have been unsuccessful due to poor response rates. Previous study showed that BRCA1 exerts regulatory control over dozens of important miRNAs that play a critical role in breast neoplasia. In addition, it established that BRCA1 regulates EGFR expression via miR-146a and provided a rationale for the development of miR-146a based therapeutic strategies. The current study further investigates the role of BRCA1 and miR-146a in regulating EGFR signaling. Analysis of The Cancer Genome Atlas (TCGA) data reveals that low expression of miR-146a is associated with distinctively poor overall survival of TNBC patients. miR-146a loss/ gain of function experiments in vitro demonstrates that BRCA1 and miR-146a regulate EGFR signaling, extracellular matrix (ECM) remodeling and chemoresistance. Using in vivo mouse models, the study further shows that miR-146a overexpression delays tumor formation leading to better overall survival. Since one miRNA can target multiple genes and regulate multiple signaling pathways, this study provides evidence to suggest that restoring miR-146a could suppress EGFR signaling and other compensatory pathways, providing a targeted therapeutic option for BRCA1 associated BLBC.