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

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...

Full description

Saved in:
Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2018-05, Vol.78 (10), p.2524-2535
Main Authors: Luan, Haitao, Mohapatra, Bhopal, Bielecki, Timothy A, Mushtaq, Insha, Mirza, Sameer, Jennings, Tameka A, Clubb, Robert J, An, Wei, Ahmed, Dena, El-Ansari, Rokaya, Storck, Matthew D, Mishra, Nitish K, Guda, Chittibabu, Sheinin, Yuri M, Meza, Jane L, Raja, Srikumar, Rakha, Emad A, Band, Vimla, Band, Hamid
Format: Article
Language:English
Subjects:
Biotechnology
Brain tumors
Breast cancer
Cathepsin B
Cell lines
Deoxyribonucleic acid
DNA
ErbB-2 protein
Gene expression
Hsc70 protein
Hsp90 protein
Transcription factors
Tumor cell lines
Tumor suppressor genes
Tumorigenesis
Ubiquitin
Ubiquitin-protein ligase
Xenografts
Zinc
Zinc finger proteins
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 oncogenic traits and 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 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. These findings reveal a novel targetable pathway of breast oncogenesis unleashed by the loss of tumor suppressor ubiquitin ligase CHIP/STUB1. .
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-16-2140