MicroRNA-29c is down-regulated in basal-like breast cancers and regulates invasion and chemosensitivity

While the basal-like subtype accounts for only a small subset of all breast cancer cases, it is associated with the worst prognosis. The majority of basal-like tumors are triple-negative (ER-, PR-, and HER2-negative), and thus lack molecular targets for therapy. To identify potential molecular markers and/or pathways that are critical to the basal-like tumor phenotype, we investigated the deregulation of microRNAs in primary breast tumors from an ethnically diverse cohort of patients. Forty-four microRNAs were identified as down-regulated in basal-like tumors compared to luminal-A tumors. MicroRNA-29c (miR-29c) was the most significantly down-regulated microRNA. In breast cancer cells in vitro, miR-29c was capable of regulating phenotypes associated with basal-like tumors such as cell invasion and drug sensitivity. Exogenous expression of miR-29c sensitizes UACC 3199 to doxorubicin-induced killing, while its inhibition leads to resistance to doxorubicin-induced killing. In addition, miR-29c decreases invasiveness of UACC-3199 cells, along with down-regulation of extracellular matrix (ECM) genes (LAMC1 and COL5A2) and ECM modifying enzyme LOXL2. In addition, miR-29c directly regulates B-MYB, an oncogene over expressed in basal-like tumors and co-expression of miR-29c and B-MYB abolishes UACC 3199 sensitivity to doxorubicin. Furthermore, our work demonstrates a regulatory role for the transcription factor GATA3 in miR-29c expression in breast cancer. Our findings support a role for miR-29c in basal-like breast tumorigenesis that is linked to drug resistance. reference VS sample