Cancer stem-like cells induce cisplatin resistance and miR-17 and miR-93 regulate p21 expression in triple-negative breast cancer

We used human breast cancer cell line MDA-MB-231 to examine the role of microRNAs (miRNAs) in regulating the expression of p21, a cyclin-dependent kinase inhibitor, and in inducing resistance to cisplatin, an anticancer drug. MDA-MB231 cells were separated into two subpopulations, i.e., cancer stem-like cells (CSCs) and cancer cells, based on the expression of cell surface antigens CD44 and CD24. P21 protein expression was higher in CSCs than in cancer cells. Exposure of MDA-MB-231 cells to cisplatin increased p21 protein expression. However, p21 expression was significantly lower in cisplatin-treated CSCs than in cisplatin-treated cancer cells, suggesting that p21-dependent cell cycle suppression was lower in CSCs than in cancer cells. Moreover, caspase-3 activity was significantly lower in cisplatin-treated CSCs than in cisplatin-treated cancer cells, indicating that CSCs were more resistant to cisplatin-induced apoptosis than cancer cells. To explore the role of miRNAs in p21 expression, MDA-MB-231 cells were treated with various miRNA inhibitors and CSCs were isolated. Treatment with miR-17 and miR-93 inhibitors increased p21 expression in CSCs, suggesting that miR-17 and miR-93 suppressed p21 expression. Thus, the results of the present study indicate that CSCs contribute to cisplatin resistance of MDA-MB231 cells and suggest that miR-17 and miR-93 inhibit the expression of p21, a factor involved in drug resistance.