Breast cancer, one of the leading causes of death in the world, has been largely considered to be drug resistant because of a small population of drug refractory cells, the cancer stem cells (CSCs). The CSCs are tightly regulated by self-renewal pathways such as the Wnt pathway, which is further regulated by a gamut of microRNAs. In this study, we investigated the effect of ursolic acid (UA), a natural triterpene, on breast CSCs enriched from breast cancer cell lines, MCF7, MDA-MB-231 and T47D and analysed the interplay of the Wnt inhibitor, sFRP4 and an miRNA, miR-499a-5p, in mediating the effect of UA. By using caspase 3/7, ROS, migration, TCF/LEF and CAM assays, overexpressing and inhibiting miR-499a-5p and NanoString PanCancer analysis, we observed that UA had significant anti-CSC ability. There was a link between UA and Wnt/β-catenin pathway wherein, Wnt was suppressed by upregulation of the antagonist, sFRP4. Furthermore, expression of the oncogenic miR-499a-5p was substantially diminished in CSCs after UA treatment. Notably, the axis by which miR-499a-5p acts is via the TCF/LEF machinery of the Wnt/β-catenin pathway. Our findings indicate for the first time that UA can target breast CSCs via Wnt by suppressing miR-499a-5p and upregulating the Wnt antagonist, sFRP4.Keywords: Breast cancer stem cells; Ursolic acid; Wnt antagonism; miRNA-499a-5p; sFRP4.

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