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Cancer Res. 2018 May 15;78(10):2524-2535. doi: 10.1158/0008-5472.CAN-16-2140. Epub 2018 Mar 6.

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

Author information

1
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.
2
Department of Genetics, University of Nebraska Medical Center, Omaha, Nebraska.
3
Department of Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska.
4
Department of Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.
5
Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
6
Department of Pathology, University of Nottingham and Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, United Kingdom.
7
Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska.
8
Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska.
9
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska. hband@unmc.edu vband@unmc.edu.
10
Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.

Abstract

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.

PMID:
29510992
PMCID:
PMC5955821
DOI:
10.1158/0008-5472.CAN-16-2140
[Indexed for MEDLINE]
Free PMC Article

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