Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion

Abhijit Mazumdar, Graham M. Poage, Jonathan Shepherd, Anna Tsimelzon, Zachary C. Hartman, Petra Den Hollander, Jamal Hill, Yun Zhang, Jenny Chang, Susan G. Hilsenbeck, Suzanne Fuqua, C. Kent Osborne, Gordon B. Mills, Powel H. Brown

    Research output: Contribution to journalArticle

    13 Scopus citations

    Abstract

    Estrogen receptor (ER)-negative cancers have a poor prognosis, and few targeted therapies are available for their treatment. Our previous analyses have identified potential kinase targets critical for the growth of ER-negative, progesterone receptor (PR)-negative and HER2-negative, or “triple-negative” breast cancer (TNBC). Because phosphatases regulate the function of kinase signaling pathways, in this study, we investigated whether phosphatases are also differentially expressed in ER-negative compared to those in ER-positive breast cancers. We compared RNA expression in 98 human breast cancers (56 ER-positive and 42 ER-negative) to identify phosphatases differentially expressed in ER-negative compared to those in ER-positive breast cancers. We then examined the effects of one selected phosphatase, dual specificity phosphatase 4 (DUSP4), on proliferation, cell growth, migration and invasion, and on signaling pathways using protein microarray analyses of 172 proteins, including phosphoproteins. We identified 48 phosphatase genes are significantly differentially expressed in ER-negative compared to those in ER-positive breast tumors. We discovered that 31 phosphatases were more highly expressed, while 11 were underexpressed specifically in ER-negative breast cancers. The DUSP4 gene is underexpressed in ER-negative breast cancer and is deleted in approximately 50 % of breast cancers. Induced DUSP4 expression suppresses both in vitro and in vivo growths of breast cancer cells. Our studies show that induced DUSP4 expression blocks the cell cycle at the G1/S checkpoint; inhibits ERK1/2, p38, JNK1, RB, and NFkB p65 phosphorylation; and inhibits invasiveness of TNBC cells. These results suggest that that DUSP4 is a critical regulator of the growth and invasion of triple-negative breast cancer cells.

    Original languageEnglish (US)
    Pages (from-to)441-454
    Number of pages14
    JournalBreast Cancer Research and Treatment
    Volume158
    Issue number3
    DOIs
    StatePublished - Aug 1 2016

    Keywords

    • MAPK pathways
    • Mouse xenograft
    • Phosphatase
    • TNBC

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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  • Cite this

    Mazumdar, A., Poage, G. M., Shepherd, J., Tsimelzon, A., Hartman, Z. C., Den Hollander, P., Hill, J., Zhang, Y., Chang, J., Hilsenbeck, S. G., Fuqua, S., Kent Osborne, C., Mills, G. B., & Brown, P. H. (2016). Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion. Breast Cancer Research and Treatment, 158(3), 441-454. https://doi.org/10.1007/s10549-016-3892-y