@article{2874ab5455df475085353306c9836313,
title = "The phosphatase PPM1A inhibits triple negative breast cancer growth by blocking cell cycle progression",
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.",
author = "Abhijit Mazumdar and Tahaney, {William M.} and {Reddy Bollu}, Lakshmi and Graham Poage and Jamal Hill and Yun Zhang and Mills, {Gordon B.} and Brown, {Powel H.}",
note = "Funding Information: Competing interests: P.H.B. served as a Scientific Advisory Board Member for the Susan G. Komen for the Cure Foundation (until 2017), and P.H.B. is a holder of GeneTex stock (<1% of the total company stock); neither of these relate to this publication. G.B.M. serves as a Consultant/Scientific Advisory Board Member for AstraZeneca, Catena Pharmaceuticals, Critical Outcome Technologies, ImmunoMET, Ionis, Signalchem Lifesciences, Symphogen, Takeda/Millenium Pharmaceuticals, and Tarveda. G.B.M. is a holder of stock/options/financial companies for Catena Pharmaceuticals, ImmunoMet, SignalChem, Spindletop Ventures, and Tarveda. G.B. M. has licensed the HRD assay to Myriad Genetics and has intellectual property on the Nanostring DSP platform. G.B.M. is sponsored by the following research companies: Adelson Medical Research Foundation, AstraZeneca, Breast Cancer Research Foundation, Immunomet, Ionis, Karus Therapeutics, Komen Research Foundation, Nanostring, Ovarian Cancer Research Foundation, Pfizer, Prospect Creek Foundation, and Takeda/Millenium Pharmaceuticals. None of these relate to this publication (G.B.M.). All remaining authors declare no actual, potential, or perceived conflict of interest that would prejudice the impartiality of this article. Funding Information: We would like to thank Michelle Savage for editing the manuscript, and Sam Short for assisting in the submission. This work was funded by a Susan G Komen Promise Grant (KG081694 P.H.B., G.B.M.), a Komen SAC grant (SAC110052, G.B.M.), and a Komen SAB grant (9SAB12-00006, P.H.B.), and a CCSG grant (P30 CA016672, P.H.B, G.B.M.). Publisher Copyright: {\textcopyright} 2019, The Author(s).",
year = "2019",
month = dec,
day = "1",
doi = "10.1038/s41523-019-0118-6",
language = "English (US)",
volume = "5",
journal = "npj Breast Cancer",
issn = "2374-4677",
publisher = "Nature Publishing Group",
number = "1",
}