J Breast Cancer.  2020 Apr;23(2):162-170. 10.4048/jbc.2020.23.e20.

Protein Phosphatase 1H, Cyclin-Dependent Kinase Inhibitor p27, and Cyclin-Dependent Kinase 2 in Paclitaxel Resistance for Triple Negative Breast Cancers

Affiliations
  • 1Interdisciplinary Program on Tumor Biology, Seoul National University College of Medicine, Seoul, Korea
  • 2Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea
  • 3Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
  • 4Department of Surgery, Seoul National University Hospital, Seoul, Korea
  • 5Division of Clinical Bioinformatics, Seoul National University Hospital, Seoul, Korea
  • 6Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
  • 7Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
  • 8Genomic Medicine Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea

Abstract

Purpose
Paclitaxel is a cytotoxic chemotherapy commonly used in patients with triple negative breast cancer (TNBC); however, the resistance to paclitaxel is a cause of poor response in the patients. The aim of this study was to examine the role of protein phosphatase 1H (PPM1H) in paclitaxel resistance in breast cancer patients.
Methods
To investigate the function of PPM1H in paclitaxel treatment, we conducted in vitro assays and molecular experiments using a stable cell line (MDA-MB-231) in which PPM1H is overexpressed. We also performed molecular analyses on patient tissue samples. Molecular expression related to PPM1H in breast cancer patients was analyzed using TCGA data.
Results
We investigated whether PPM1H was associated with paclitaxel resistance in breast cancer. PPM1H expression was upregulated in breast cancer cells treated with paclitaxel. We also observed that overexpression of PPM1H in breast cancer cells resulted in increased sensitivity to paclitaxel in vitro. Additionally, paclitaxel treatment induced dephosphorylation of cyclin-dependent kinase (CDK) inhibitor p27 (p27), which was more evident in PPM1H-overexpressing cells. To understand how upregulation of PPM1H increases paclitaxel sensitivity, we determined the levels of p27, phospho-p27, and CDK2, since CDK2 exerts antagonistic effects against PPM1H on p27 phosphorylation. The patient-derived xenograft (PDX) tumors that did not respond to paclitaxel showed increased levels of CDK2 and phospho-p27 and decreased levels of total p27 compared to the other breast tumor tissues. The use of dinaciclib, a selective CDK inhibitor, significantly inhibited tumor growth in the PDX model.
Conclusion
CDK2 kinase activity was significantly upregulated in basal breast cancer tumors and was negatively correlated with p27 protein levels in the TCGA breast cancer dataset, suggesting that targeting CDK2 may be an effective treatment strategy for TNBC patients.

Keyword

Cyclin-dependent kinase 2; Cyclin-dependent kinase inhibitor p27; Paclitaxel; PPM1H protein
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