Collectively, the findings presented in this study elucidate functional and mechanistic roles for the KIFC2-USP9X/CDK4 signaling axis in promoting growth and resistance to ET and CDK4/6 inhibitors in HR+/HER2– BC and highlight KIFC2 as a potential therapeutic target and predictive biomarker for therapeutic responsiveness in these patients. Here, ERBB2 is linked to breast cancer.