IQGAP1 Protein Binds Human Epidermal Growth Factor Receptor 2 (HER2) and Modulates Trastuzumab Resistance

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2011 Jul 5

PMID 21724847

Citations 31

Authors

Colin D White

Zhigang Li

Deborah A Dillon

David B Sacks

Affiliations

Soon will be listed here.

Abstract

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20-25% of breast cancers. Increased HER2 expression is an adverse prognostic factor and correlates with decreased patient survival. HER2-positive (HER2(+)) breast cancer is treated with trastuzumab. Unfortunately, some patients are intrinsically refractory to therapy, and many who do respond initially become resistant within 1 year. Understanding the molecular mechanisms underlying HER2 signaling and trastuzumab resistance is essential to reduce breast cancer mortality. IQGAP1 is a ubiquitously expressed scaffold protein that contains multiple protein interaction domains. By regulating its binding partners IQGAP1 integrates signaling pathways, several of which contribute to breast tumorigenesis. We show here that IQGAP1 is overexpressed in HER2(+) breast cancer tissue and binds directly to HER2. Knockdown of IQGAP1 decreases HER2 expression, phosphorylation, signaling, and HER2-stimulated cell proliferation, effects that are all reversed by reconstituting cells with IQGAP1. Reducing IQGAP1 up-regulates p27, and blocking this increase attenuates the growth inhibitory effects of IQGAP1 knockdown. Importantly, IQGAP1 is overexpressed in trastuzumab-resistant breast epithelial cells, and reducing IQGAP1 both augments the inhibitory effects of trastuzumab and restores trastuzumab sensitivity to trastuzumab-resistant SkBR3 cells. These data suggest that inhibiting IQGAP1 function may represent a rational strategy for treating HER2(+) breast carcinoma.

Citing Articles

Mechanisms of resistance to trastuzumab in HER2-positive gastric cancer.

Li Z, Zhao H, Hu H, Shang H, Ren Y, Qiu W Chin J Cancer Res. 2024; 36(3):306-321.

PMID: 38988489 PMC: 11230884. DOI: 10.21147/j.issn.1000-9604.2024.03.07.

The IQGAP scaffolds: Critical nodes bridging receptor activation to cellular signaling.

Thines L, Roushar F, Hedman A, Sacks D J Cell Biol. 2023; 222(6).

PMID: 37071417 PMC: 10120595. DOI: 10.1083/jcb.202205062.

IQGAP1 Is a Phosphotyrosine-Regulated Scaffold for SH2-Containing Proteins.

Thines L, Li Z, Sacks D Cells. 2023; 12(3).

PMID: 36766826 PMC: 9913818. DOI: 10.3390/cells12030483.

N-Linked Glycosylation in Chinese Hamster Ovary Cells Is Critical for Insulin-like Growth Factor 1 Signaling.

Salvi R, Kumar C, Brahmbhatt K, Subedi R, Idicula-Thomas S, Madan T Int J Mol Sci. 2022; 23(23).

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CDC42-IQGAP Interactions Scrutinized: New Insights into the Binding Properties of the GAP-Related Domain.

Mosaddeghzadeh N, Pudewell S, Bazgir F, Kazemein Jasemi N, Krumbach O, Gremer L Int J Mol Sci. 2022; 23(16).

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