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.