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Updated: Oct 22, 2025

In Vitro Analysis of E3 Ubiquitin Ligase Function
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CHIP/STUB1 Ubiquitin Ligase Functions as a Negative Regulator of ErbB2 by Promoting Its Early Post-Biosynthesis

Haitao Luan1,2,3, Tameka A Bailey1, Robert J Clubb1

  • 1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Cancers
|August 27, 2021
PubMed

Insights

The C-terminus of HSC70-Interacting protein (CHIP) degrades overexpressed ErbB2 (HER2) in breast cancer cells. Loss of CHIP increases ErbB2, making cancers responsive to combined Trastuzumab and endoplasmic reticulum stress therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Overexpression of ErbB2 (HER2) drives oncogenesis in a significant portion of invasive breast cancers.
  • Cell surface expression of ErbB2 is crucial for its oncogenic activity, but the mechanisms regulating its display are not fully understood.
  • ErbB2 stability and function depend on the HSP90 molecular chaperone.

Purpose of the Study:

  • To investigate the role of CHIP (C-terminus of HSC70-Interacting protein) in regulating cell surface ErbB2 levels.
  • To identify novel mechanisms controlling ErbB2 cell surface expression in breast cancer.
  • To explore therapeutic strategies targeting ErbB2-overexpressing breast cancers with reduced CHIP expression.

Main Methods:

  • Utilized knockdown and overexpression studies to assess CHIP's effect on ErbB2.
  • Investigated the ubiquitin/proteasome-dependent degradation pathway in the endoplasmic reticulum and Golgi.
  • Analyzed endoplasmic reticulum stress responses in breast cancer cells with varying CHIP expression levels.
  • Evaluated the synergistic effects of Bortezomib and Trastuzumab on cancer cell proliferation.

Main Results:

  • CHIP targets newly synthesized, HSP90/HSC70-associated ErbB2 for degradation, thereby negatively regulating cell surface ErbB2 levels.
  • Loss of CHIP expression in ErbB2-overexpressing breast cancers correlates with increased endoplasmic reticulum stress.
  • Combined treatment with Bortezomib and Trastuzumab demonstrated synergistic inhibition of ErbB2-overexpressing breast cancer cell proliferation.

Conclusions:

  • CHIP acts as a novel negative regulator of cell surface ErbB2 expression in breast cancer.
  • Reduced CHIP expression may identify ErbB2-overexpressing breast cancers that are sensitive to combined Trastuzumab and endoplasmic reticulum stress-inducing agents.
  • These findings offer new insights into ErbB2 regulation and suggest a potential therapeutic approach for specific breast cancer subtypes.
Keywords:
BortezomibCHIP/STUB1E3ErbB2GolgiTrastuzumabbreast cancerdegradationendoplasmic reticulumpulse-chaseubiquitinubiquitin ligase

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