The Role of IQGAP1 in Breast Carcinoma
Annual summary 15 Sep 2010-14 Sep 2011
BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA
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HER2 is overexpressed in 25 of breast carcinomas. Overexpression of HER2 is an adverse prognostic feature and correlates with shorter disease-free and overall survival. HER2 breast cancer is treated with trastuzumab but many patients do not respond. Of those who do, most become refractory to therapy and progress to metastatic disease. An insight into the molecular mechanisms underlying HER2 signaling and trastuzumab resistance is essential to reduce breast cancer morbidity and mortality. IQGAP1 is a ubiquitously expressed scaffold protein that contains multiple protein interaction domains. Through interaction with its binding partners, IQGAP1 integrates diverse signaling pathways, several of which are relevant to breast tumorigenesis. The purpose of this proposal is to elucidate the function of selected IQGAP1 binding interactions in breast neoplasia. During Years 1 and 2 of this fellowship, we have shown 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 upregulates 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.
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