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

Justin M. Balko, Luis J. Schwarz, Neil E. Bhola, Richard Kurupi, Phillip Owens, Todd W. Miller, Henry Gómez, Rebecca S. Cook, Carlos L. Arteaga

Research output: Contribution to journalArticle

69 Citations (Scopus)

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 MEKdependent 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.

Original languageEnglish (US)
Pages (from-to)6346-6358
Number of pages13
JournalCancer Research
Volume73
Issue number20
DOIs
StatePublished - Oct 15 2013

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Dual-Specificity Phosphatases
Neoplastic Stem Cells
Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase Kinases
Breast Neoplasms
Phenotype
Phosphotransferases
Population
Drug Therapy
Interleukin-8
Interleukin-6
Neoplasms
Transcription Factors
Therapeutics
Apoptosis
Cytokines
Recurrence
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Activation of MAPK pathways due to DUSP4 loss promotes cancer stem cell-like phenotypes in basal-like breast cancer. / Balko, Justin M.; Schwarz, Luis J.; Bhola, Neil E.; Kurupi, Richard; Owens, Phillip; Miller, Todd W.; Gómez, Henry; Cook, Rebecca S.; Arteaga, Carlos L.

In: Cancer Research, Vol. 73, No. 20, 15.10.2013, p. 6346-6358.

Research output: Contribution to journalArticle

Balko, JM, Schwarz, LJ, Bhola, NE, Kurupi, R, Owens, P, Miller, TW, Gómez, H, Cook, RS & Arteaga, CL 2013, 'Activation of MAPK pathways due to DUSP4 loss promotes cancer stem cell-like phenotypes in basal-like breast cancer', Cancer Research, vol. 73, no. 20, pp. 6346-6358. https://doi.org/10.1158/0008-5472.CAN-13-1385
Balko, Justin M. ; Schwarz, Luis J. ; Bhola, Neil E. ; Kurupi, Richard ; Owens, Phillip ; Miller, Todd W. ; Gómez, Henry ; Cook, Rebecca S. ; Arteaga, Carlos L. / Activation of MAPK pathways due to DUSP4 loss promotes cancer stem cell-like phenotypes in basal-like breast cancer. In: Cancer Research. 2013 ; Vol. 73, No. 20. pp. 6346-6358.
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