Loss of the Nuclear Pool of Ubiquitin Ligase CHIP/STUB1 in Breast Cancer Unleashes the MZF1-Cathepsin Pro-oncogenic Program.

Autor:	Luan H; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.; Department of Genetics, University of Nebraska Medical Center, Omaha, Nebraska.; Department of Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska.; Department of Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China., Mohapatra B; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.; Department of Genetics, University of Nebraska Medical Center, Omaha, Nebraska.; Department of Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska., Bielecki TA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska., Mushtaq I; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.; Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska., Mirza S; Department of Genetics, University of Nebraska Medical Center, Omaha, Nebraska., Jennings TA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska., Clubb RJ; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska., An W; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.; Department of Genetics, University of Nebraska Medical Center, Omaha, Nebraska.; Department of Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska., Ahmed D; Department of Pathology, University of Nottingham and Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, United Kingdom., El-Ansari R; Department of Pathology, University of Nottingham and Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, United Kingdom., Storck MD; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska., Mishra NK; Department of Genetics, University of Nebraska Medical Center, Omaha, Nebraska.; Department of Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska., Guda C; Department of Genetics, University of Nebraska Medical Center, Omaha, Nebraska.; Department of Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska., Sheinin YM; Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska., Meza JL; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska.; Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska., Raja S; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska., Rakha EA; Department of Pathology, University of Nottingham and Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, United Kingdom., Band V; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska. hband@unmc.edu vband@unmc.edu.; Department of Genetics, University of Nebraska Medical Center, Omaha, Nebraska.; Department of Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska.; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska.; Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska., Band H; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska. hband@unmc.edu vband@unmc.edu.; Department of Genetics, University of Nebraska Medical Center, Omaha, Nebraska.; Department of Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska.; Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska.; Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2018 May 15; Vol. 78 (10), pp. 2524-2535. Date of Electronic Publication: 2018 Mar 06.
DOI:	10.1158/0008-5472.CAN-16-2140
Abstrakt:	CHIP/STUB1 ubiquitin ligase is a negative co-chaperone for HSP90/HSC70, and its expression is reduced or lost in several cancers, including breast cancer. Using an extensive and well-annotated breast cancer tissue collection, we identified the loss of nuclear but not cytoplasmic CHIP to predict more aggressive tumorigenesis and shorter patient survival, with loss of CHIP in two thirds of ErbB2 + and triple-negative breast cancers (TNBC) and in one third of ER + breast cancers. Reduced CHIP expression was seen in breast cancer patient-derived xenograft tumors and in ErbB2 + and TNBC cell lines. Ectopic CHIP expression in ErbB2 + lines suppressed in vitro oncogenic traits and in vivo xenograft tumor growth. An unbiased screen for CHIP-regulated nuclear transcription factors identified many candidates whose DNA-binding activity was up- or downregulated by CHIP. We characterized myeloid zinc finger 1 (MZF1) as a CHIP target, given its recently identified role as a positive regulator of cathepsin B/L (CTSB/L)-mediated tumor cell invasion downstream of ErbB2. We show that CHIP negatively regulates CTSB/L expression in ErbB2 + and other breast cancer cell lines. CTSB inhibition abrogates invasion and matrix degradation in vitro and halts ErbB2 + breast cancer cell line xenograft growth. We conclude that loss of CHIP remodels the cellular transcriptome to unleash critical pro-oncogenic pathways, such as the matrix-degrading enzymes of the cathepsin family, whose components can provide new therapeutic opportunities in breast and other cancers with loss of CHIP expression. Significance: These findings reveal a novel targetable pathway of breast oncogenesis unleashed by the loss of tumor suppressor ubiquitin ligase CHIP/STUB1. Cancer Res; 78(10); 2524-35. ©2018 AACR . (©2018 American Association for Cancer Research.)
Databáze:	MEDLINE
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