title: Activation of MAPK pathways due to DUSP4 loss promotes cancer stem cell-like phenotypes in basal-like breast cancer.
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.
authors: Authors' Affiliations: Departments of Medicine and Cancer Biology; Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee; Instituto Nacional de Enfermedades Neoplásicas, Lima, Perú; and Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors: Justin M
authors: JM
authors: Balko
authors: Luis J
authors: LJ
authors: Schwarz
authors: Neil E
authors: NE
authors: Bhola
authors: Richard
authors: R
authors: Kurupi
authors: Phillip
authors: P
authors: Owens
authors: Todd W
authors: TW
authors: Miller
authors: Henry
authors: H
authors: Gómez
authors: Rebecca S
authors: RS
authors: Cook
authors: Carlos L
authors: CL
authors: Arteaga
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018929:Cell Culture Techniques; D054637:Dual-Specificity Phosphatases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005260:Female; D064593:Heterografts; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D014162:Transfection
chemical_list: D020928:Mitogen-Activated Protein Kinases; D054639:Mitogen-Activated Protein Kinase Phosphatases; C490583:DUSP4 protein, human; D054637:Dual-Specificity Phosphatases
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