Activation of MAPK pathways due to DUSP4 loss promotes cancer stem cell-like phenotypes in basal-like breast cancer

Basal-like breast cancer (BLBC) is an aggressive disease that lacks a clinically-approved targeting therapy. Traditional chemotherapy is effective in BLBC, but it spares the cancer stem cell (CSC)-like population which is likely to contribute to cancer recurrence after the initial treatment. DUSP4 is a negative regulator of the MAPK pathway that is deficient in highly aggressive BLBCs treated with chemotherapy, leading to aberrant MAPK activation and resistance to taxane-induced apoptosis. Herein, we investigated how DUSP4 regulates the MEK and JNK pathways in modifying CSC-like behavior. DUSP4 loss increased mammosphere formation and the expression of the CSC-promoting cytokines IL-6 and IL-8. These effects were caused in part by loss of control of the MEK and JNK pathways and involved downstream activation of the ETS-1 and c-JUN transcription factors. Enforced expression of DUSP4 in reduced the CD44+/CD24- population in multiple BLBC cell lines in a MEK-dependent manner, limiting tumor formation of claudin-low SUM159PT cells in mice. Our findings support the evaluation of MEK and JNK pathway inhibitors as therapeutic agents in BLBC in order to eliminate the CSC population.