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

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

doi:10.1038/s41523-019-0118-6

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.

Highlights

Breast cancer is one of the most commonly diagnosed cancers in women, and was the second-leading cause of cancer-related death in women in the United States in 2017.1 Most breast cancers are estrogen receptor (ER)-positive, which have a relatively good prognosis
We have identified phosphatases that are overexpressed in triple negative” breast cancers (TNBCs) when compared to ER-positive breast cancer, some of which are critical for the growth of TNBC cells
We focused on the PPM1A phosphatase that is underexpressed in ERnegative breast cancers

Summary

Introduction

Breast cancer is one of the most commonly diagnosed cancers in women, and was the second-leading cause of cancer-related death in women in the United States in 2017.1 Most breast cancers are estrogen receptor (ER)-positive, which have a relatively good prognosis. Selective estrogen receptor modulators (e.g., tamoxifen) and aromatase inhibitors (e.g., anatrozole, letrozole, and exemestane) are currently used for the treatment of these ERpositive breast cancers either alone or in combination with chemotherapy.[2,3,4,5,6] Alternatively, ER-negative HER2-positive breast cancers can be treated with anti-HER2 drugs, (e.g., trastuzumab and lapatinib[7,8,9]). PTP4A3, one of the identified phosphatases, is a critical regulator of TNBC tumor growth in vivo.[12] In the current study, we investigated the role of another key phosphatase that is differentially expressed in ER-negative tumors in regulating breast cancer survival and growth. Using cBioPortal[14,15] and the Molecular

Methods

Results

Conclusion