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

Saem Hur; Ju Hee Kim; Jihui Yun; Young Wook Ju; Jong Min Han; 허우행; Kwangsoo Kim; 정경훈; Han-Byoel Lee; Wonshik Han; Dong-Young Noh; Jong-Il Kim; Hyeong-Gon Moon

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저자정보: Saem Hur (Interdisciplinary Program on Tumor Biology Seoul National University College of Medicine Seoul Ko) Ju Hee Kim (Biomedical Research Institute Seoul National University Hospital Seoul Korea) Jihui Yun (Department of Biomedical Sciences Seoul National University College of Medicine Seoul Korea) Young Wook Ju (Department of Surgery Seoul National University Hospital Seoul Korea) Jong Min Han (Interdisciplinary Program on Tumor Biology Seoul National University College of Medicine Seoul Ko) 허우행 (서울대학교) Kwangsoo Kim (Division of Clinical Bioinformatics Seoul National University Hospital Seoul Korea) 정경훈 (서울대학교병원) Han-Byoel Lee (Department of Surgery Seoul National University Hospital Seoul Korea) Wonshik Han (Departments of Surgery and Internal Medicine Seoul National University College of Medicine Seoul Ko) Dong-Young Noh (Department of Surgery Seoul National University College of Medicine Cancer Research Institute Seoul) Jong-Il Kim (Department of Biomedical Sciences Seoul National University College of Medicine Seoul Korea) Hyeong-Gon Moon (Department of Surgery Seoul National University College of Medicine Seoul Korea)

저널정보: 한국유방암학회 Journal of Breast Cancer Journal of Breast Cancer Vol.23 No.2

발행연도: 2020.1

수록면: 162 - 170 (9page)

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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.

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

참고문헌 (19)

참고문헌 신청

Torre LA / 2016 / Global cancer incidence and mortality rates and trends--An update / Cancer Epidemiol Biomarkers Prev 25:16~27

Early Breast Cancer Trialists' Collaborative Group(EBCTCG) / 2018 / Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer : meta-analysis of individual patient data from ten randomised trials / Lancet Oncol 19:27~39

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Saem Hur

소속기관 Interdisciplinary Program on Tumor Biology Seoul National University College of Medicine Seoul Ko