The microRNA miR-181c enhances chemosensitivity and reduces chemoresistance in breast cancer cells via down-regulating osteopontin

Acquired resistance to chemotherapy is a frequent challenge in cancer care and one of the leading causes for failing breast cancer therapies. There is accumulative clinical and experimental evidence indicating that microRNAs (miRNAs) play a crucial role in developing therapeutic resistance in cancer cells. We aimed to explore key miRNAs and associated mechanisms by which breast cancer develops chemoresistance. In this study, we found that a particular miRNA species, miR-181c, was significantly low-expressed in breast cancer cell line MCF-7 which developed chemoresistance towards doxorubicin (Adriamycin, ADR, subclone renamed as MCF-7/ADR) than in the wild-type MCF-7 cells. Induced overexpression of miR-181c significantly inhibited cell proliferation, reversed the chemoresistance towards doxorubicin, and reduced the growth of resistant breast cancer xenograft tumors in vitro and in vivo. Using a bioinformatics approach, we also identified osteopontin (OPN) as a direct target of miR-181c. In contrast to low miR-181c expression in MCF-7/ADR cells, OPN showed a reversely high expression in resistant MCF-7/ADR cells. Our results suggest that miR-181c may regulate chemosensitivity and chemoresistance by downregulating OPN, resulting in enhanced p53-dependent transactivation and apoptosis in resistant breast cancer cells. This study provides new insights to develop effective interventions for cancer patients with acquired resistance to chemotherapy. (C) 2018 Published by Elsevier B.V.