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

Abstract: There is compelling evidence that cancer stem cells (CSCs) play an essential role in failure of conventional antitumor therapy. In breast cancer, CD24-/low/CD44+ phenotype as well as a high aldehyde dehydrogenase activity (ALDH+) are widely associated with CSC subtypes. Furthermore, CD24-/low/CD44+ pattern is also characteristic of the mesenchymal cells generated by an epithelial-mesenchymal transition (EMT). CD24 is a surface marker expressed in many tumor types, however, its biological functions and role in cancer progression and treatment resistance remain poorly documented. We have previously shown that loss of CD24 expression in breast cancer cells is associated with radiation resistance, in relationship with the control of oxidative stress. Because ROS are known to mediate the effects of anticancer drugs as well as ionizing radiation, we investigated if CD24 could be defined as an actor of both radiation- and chemo-resistance of breast cancer cells. Using the HMLE breast cancer cell model, we observed that loss of CD24 expression induces stemness properties associated with the acquisition of a hybrid E/M phenotype. The CD24-/low cells were intrinsically more resistant than CD24+ cells. The resistance was linked to a lower level of ROS, and CD24 controlled ROS levels through the regulation of mitochondrial functions independently of antioxidant activity. Together, these results suggest a key role of CD24 in de-differentiation process of breast cancer cells, promoting acquisition of therapeutic resistance properties.