Identification of KIF20A as a vulnerability for breast cancer stem-like cells in triple negative breast cancer

Triple-negative breast cancer (TNBC), being both aggressive and highly lethal, poses a significant challenge in terms of treatment. Its heterogeneity and lack of hormone receptors or HER2 expression further restrict the availability of targeted therapy. Breast cancer stem cells (BCSCs), known to fuel TNBC malignancy, are now being exploited as the vulnerability for TNBC treatment. Here, we dissected the transcriptome of BCSCs and identified Kinesin Family Member 20A (KIF20A) as an essential gene for BCSC survival and TNBC tumorigenesis. Depletion or pharmacologic inhibition of KIF20A impairs BCSC viability, tumor initiation and development in vitro and in vivo. Mechanistically, KIF20A regulates BCSC stemness through modulating the oxidative phosphorylation (OXPHOS) pathway in mitochondria, which is repressed by a member of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, SMARCA4. Therapeutically, treatment with a KIF20A inhibitor sensitizes TNBC xenograft tumors to standard-of-care chemotherapy. Our study highlights the significance of targeting KIF20A to exploit BCSC vulnerabilities in TNBC. Overall design: RNA-seq analyses between breast cancer stem cells (BCSCs) and non-BCSCs from Hs578T and HCC70 cells. RNA-seq analyses between control sgRNA (sgCtrl) and KIF20A sg1, or KIF20A overexpression (OE) and empty vector (EV) in MDA-MB-231 cells.