Loss of CD24 promotes radiation­ and chemo­resistance by inducing stemness properties associated with a hybrid E/M state in breast cancer cells.

Cancer stem cells (CSCs) serve an essential role in failure of conventional antitumor therapy. In breast cancer, CD24­/low/CD44+ phenotype and high aldehyde dehydrogenase activity are associated with CSC subtypes. Furthermore, CD24­/low/CD44+ pattern is also characteristic of mesenchymal cells generated by epithelial­mesenchymal transition (EMT). CD24 is a surface marker expressed in numerous types of tumor, however, its biological functions and role in cancer progression and treatment resistance remain poorly documented. Loss of CD24 expression in breast cancer cells is associated with radiation resistance and control of oxidative stress. Reactive oxygen species (ROS) mediate the effects of anticancer drugs as well as ionizing radiation; therefore, the present study investigated if CD24 mediates radiation­ and chemo­resistance of breast cancer cells. Using a HMLE breast cancer cell model, CD24 expression has been artificially modulated and it was observed that loss of CD24 expression induced stemness properties associated with acquisition of a hybrid E/M phenotype. CD24­/low cells were more radiation­ and chemo­resistant than CD24+ cells. The resistance was associated with lower levels of ROS; CD24 controlled ROS levels via regulation of mitochondrial function independently of antioxidant activity. Together, these results suggested a key role of CD24 in de­differentiation of breast cancer cells and promoting acquisition of therapeutic resistance properties.