Translocation of intracellular CD24 constitutes a triggering event for drug resistance in breast cancer

The capacity of tumor cells to shift dynamically between different states could be responsible for chemoresistance and has been commonly linked to the acquisition of stem cell properties. Here, we have evaluated the phenotype switching associated with drug resistance in breast cancer cell lines and cell lineage obtained from Brazilian patients. We have highlighted the role of the cancer stem cell marker CD24 in the dynamics of cell plasticity and the acquirement of drug resistance. We showed that the translocation of CD24 from cytosol to cell membrane is a triggering event for the phenotype change of breast tumor cells exposed to drug stress. Here, we provide evidence that the phenotype switching is due to the presence of a cytosolic pool of CD24. Importantly, the cellular localization of CD24 was correlated with the changes in the dynamics of p38 MAPK activation. A strong and continuous phosphorylation of the p38 MAPK led to the overexpression of Bcl-2 after treatment in persistent cells presenting high density of CD24 on cell membrane. This phenotype enabled the cells to enter in slow-down of cell cycle, after which several weeks later, the dormant cells proliferated again. Importantly, the use of a p38 activity inhibitor sensitized cells to drug treatment and avoided chemoresistance.

Automated summary

The study revealed that the translocation of CD24 in breast cancer cells is correlated with drug resistance and the dynamics of p38 MAPK activation. The movement of CD24 from cytosol to cell membrane is a key event triggering phenotype change in breast tumor cells. Over-phosphorylation of p38 MAPK on the high-density CD24 cell membrane led to overexpression of Bcl-2 and entry into a slow-down cell cycle, followed by cell proliferation weeks later.