Activation of MAPK pathways due to DUSP4 loss promotes cancer stem cell-like phenotypes in basal-like breast cancer.
Cancer Res, 2013/10/15;73(20):6346-58.
Balko JM[1], Schwarz LJ, Bhola NE, Kurupi R, Owens P, Miller TW, Gómez H, Cook RS, Arteaga CL
Affiliations
PMID: 23966295DOI: 10.1158/0008-5472.CAN-13-1385
Impact factor: 13.312
Abstract
Basal-like breast cancer (BLBC) is an aggressive disease that lacks a clinically approved targeted 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. Dual specificity phosphatase-4 (DUSP4) is a negative regulator of the mitogen-activated protein kinase (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 MAP-ERK kinase (MEK) and c-jun-NH2-kinase (JNK) pathways in modifying CSC-like behavior. DUSP4 loss increased mammosphere formation and the expression of the CSC-promoting cytokines interleukin (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 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 to eliminate the CSC population.
MeSH terms
Animals; Breast Neoplasms; Cell Culture Techniques; Dual-Specificity Phosphatases; Female; Heterografts; Humans; MAP Kinase Signaling System; Mice; Mice, Nude; Mitogen-Activated Protein Kinase Phosphatases; Mitogen-Activated Protein Kinases; Neoplastic Stem Cells; Phenotype; Transfection
More resources
Full text:
Europe PubMed Central; PubMed Central
EndNote: Download