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.
Highlights
The ubiquitin-proteasome system (UPS) plays diverse roles in normal cellular homeostasis
As previous small studies [11,12,13] have not clarified which breast cancer subtypes lose C-terminus of HSC70-interacting protein (CHIP) expression, we performed IHC analysis of formalin-fixed and paraffin-embedded Tissue microarrays (TMA) from a well-annotated cohort of 971 breast cancer patients (Supplementary Table S1; refs. 23–27) using an established rabbit anti-CHIP antibody [15] further validated in Western blotting with lysates of CHIP-depleted or ectopic CHIP-expressing cell lines (Supplementary Fig. S1)
Loss of expression of the HSP90/HSC70 co-chaperone CHIP E3 has emerged as a mechanism to promote tumor progression
Summary
The ubiquitin-proteasome system (UPS) plays diverse roles in normal cellular homeostasis. Ubiquitination involves two ubiquitin-activating (E1) enzymes, a small group of ubiquitinconjugating (E2) enzymes and a large repertoire of ubiquitin ligase (E3) enzymes. E3s dictate substrate specificity and comprise two broad groups: the human papilloma virus E6-interacting (HECT) domain and the Really Interesting New Gene (RING) finger domain protein families [1]. Consistent with roles of UPS in oncogenesis, certain cancers, for example, multiple myeloma, are clinically treated with proteasome inhibitors [1]. Recent focus has shifted to substrate-specific elements of the UPS, such as E3s, with MDM2 inhibitors currently in clinical trials for several malignancies (www.clinicaltrials.gov). Mutations of E3s, such as CBL [2] or FBW7 [3] convert them into oncogenes
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