The phosphatase PPM1A inhibits triple negative breast cancer growth by blocking cell cycle progression

Abhijit Mazumdar, William M. Tahaney, Lakshmi Reddy Bollu, Graham Poage, Jamal Hill, Yun Zhang, Gordon Mills, Powel H. Brown

    Research output: Contribution to journalArticle

    Abstract

    Estrogen receptor (ER)-negative, progesterone receptor (PR)-negative and HER2-negative, or “triple negative,” breast cancer (TNBC) is a poor prognosis clinical subtype that occurs more frequently in younger women and is commonly treated with toxic chemotherapy. Effective targeted therapy for TNBC is urgently needed. Our previous studies have identified several kinases critical for TNBC growth. Since phosphatases regulate the function of kinase signaling pathways, we sought to identify critical growth-regulatory phosphatases that are expressed differentially in ER-negative, as compared to ER-positive, breast cancers. In this study, we examined the role of one of these differentially expressed phosphatases, the protein phosphatase Mg + 2/Mn + 2 dependent 1A (PPM1A) which is underexpressed in ER-negative breast cancer as compared to ER-positive breast cancers, in regulating TNBC growth. We found that PPM1A is deleted in ~40% of ER-negative breast cancers, and that induced expression of PPM1A suppresses in vitro and in vivo growth of TNBC cells. This study demonstrates that induction of PPM1A expression blocks the cell cycle and reduces CDK and Rb phosphorylation. These results suggest PPM1A is a crucial regulator of cell cycle progression in triple negative breast cancer. Our results also suggest that PPM1A loss should be explored as a predictive biomarker of CDK inhibitor sensitivity.

    Original languageEnglish (US)
    Article number22
    Journalnpj Breast Cancer
    Volume5
    Issue number1
    DOIs
    StatePublished - Dec 1 2019

    Fingerprint

    Triple Negative Breast Neoplasms
    Protein Phosphatase 2
    Phosphoric Monoester Hydrolases
    Estrogen Receptors
    Cell Cycle
    Growth
    Breast Neoplasms
    Phosphotransferases
    Poisons
    Progesterone Receptors
    Biomarkers
    Phosphorylation
    Drug Therapy

    ASJC Scopus subject areas

    • Oncology
    • Radiology Nuclear Medicine and imaging
    • Pharmacology (medical)

    Cite this

    Mazumdar, A., Tahaney, W. M., Reddy Bollu, L., Poage, G., Hill, J., Zhang, Y., ... Brown, P. H. (2019). The phosphatase PPM1A inhibits triple negative breast cancer growth by blocking cell cycle progression. npj Breast Cancer, 5(1), [22]. https://doi.org/10.1038/s41523-019-0118-6

    The phosphatase PPM1A inhibits triple negative breast cancer growth by blocking cell cycle progression. / Mazumdar, Abhijit; Tahaney, William M.; Reddy Bollu, Lakshmi; Poage, Graham; Hill, Jamal; Zhang, Yun; Mills, Gordon; Brown, Powel H.

    In: npj Breast Cancer, Vol. 5, No. 1, 22, 01.12.2019.

    Research output: Contribution to journalArticle

    Mazumdar, Abhijit ; Tahaney, William M. ; Reddy Bollu, Lakshmi ; Poage, Graham ; Hill, Jamal ; Zhang, Yun ; Mills, Gordon ; Brown, Powel H. / The phosphatase PPM1A inhibits triple negative breast cancer growth by blocking cell cycle progression. In: npj Breast Cancer. 2019 ; Vol. 5, No. 1.
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    abstract = "Estrogen receptor (ER)-negative, progesterone receptor (PR)-negative and HER2-negative, or “triple negative,” breast cancer (TNBC) is a poor prognosis clinical subtype that occurs more frequently in younger women and is commonly treated with toxic chemotherapy. Effective targeted therapy for TNBC is urgently needed. Our previous studies have identified several kinases critical for TNBC growth. Since phosphatases regulate the function of kinase signaling pathways, we sought to identify critical growth-regulatory phosphatases that are expressed differentially in ER-negative, as compared to ER-positive, breast cancers. In this study, we examined the role of one of these differentially expressed phosphatases, the protein phosphatase Mg + 2/Mn + 2 dependent 1A (PPM1A) which is underexpressed in ER-negative breast cancer as compared to ER-positive breast cancers, in regulating TNBC growth. We found that PPM1A is deleted in ~40{\%} of ER-negative breast cancers, and that induced expression of PPM1A suppresses in vitro and in vivo growth of TNBC cells. This study demonstrates that induction of PPM1A expression blocks the cell cycle and reduces CDK and Rb phosphorylation. These results suggest PPM1A is a crucial regulator of cell cycle progression in triple negative breast cancer. Our results also suggest that PPM1A loss should be explored as a predictive biomarker of CDK inhibitor sensitivity.",
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