Loss of WWOX contributes to cisplatin resistance in triple-negative breast cancer cells by modulating miR-182 and miR-214.

Abstract

WW domain-containing oxidoreductase (WWOX) loss frequently occurs in triple-negative breast cancer (TNBC). WWOX loss enhances cisplatin resistance in TNBC patients. Although WWOX loss has an effect on the selection of a DNA repair pathway that contributes to enhanced mutagenesis, the downstream expression changes in resistant cancer cells have not been fully explored. This study aimed to investigate the potential role of microRNAs (miRNAs) in the regulation of cisplatin resistance in WWOX-deficient TNBC cells. Transient transfections were performed to overexpress WWOX in MDA-MB-231 cells. WWOX-overexpressing MDA-MB-231 cells were determined by western blot. Expression profiling of the miRNA was assessed via real-time polymerase chain reaction. miRNA expression profiling of WWOX-deficient and -sufficient MDA-MB-231 cells revealed that miR-182 upregulation and miR-214 downregulation were markedly positively associated with cisplatin resistance of WWOX-deficient MDA-MB-231 cells. An elevated expression of miR-182 and decreased expression of miR-214 may contribute to cisplatin resistance in WWOX-absent MDA-MB-231 cells by signaling pathway dysregulation of DNA repair/apoptosis/ protein kinase B (AKT). The results emphasize that WWOX deficiency promotes resistance to cisplatin in TNBC cells and the possible predicting biomarker of WWOX for resistance to cisplatin.