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Clin Cancer Res. 2018 Oct 15;24(20):5165-5177. doi: 10.1158/1078-0432.CCR-18-0279. Epub 2018 Jun 25.

Loss of E-cadherin Enhances IGF1-IGF1R Pathway Activation and Sensitizes Breast Cancers to Anti-IGF1R/InsR Inhibitors.

Author information

1
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
2
Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee Women's Research Institute, Pittsburgh, Pennsylvania.
3
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
4
The Center for Precision Environmental Health, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
5
Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania.
6
Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
7
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania. leeav@upmc.edu.
8
Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania.

Abstract

Purpose: Insulin-like growth factor 1 (IGF1) signaling regulates breast cancer initiation and progression and associated cancer phenotypes. We previously identified E-cadherin (CDH1) as a repressor of IGF1 signaling and in this study examined how loss of E-cadherin affects IGF1R signaling and response to anti-IGF1R/insulin receptor (InsR) therapies in breast cancer.Experimental Design: Breast cancer cell lines were used to assess how altered E-cadherin levels regulate IGF1R signaling and response to two anti-IGF1R/InsR therapies. In situ proximity ligation assay (PLA) was used to define interaction between IGF1R and E-cadherin. TCGA RNA-seq and RPPA data were used to compare IGF1R/InsR activation in estrogen receptor-positive (ER+) invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) tumors. ER+ ILC cell lines and xenograft tumor explant cultures were used to evaluate efficacy to IGF1R pathway inhibition in combination with endocrine therapy.Results: Diminished functional E-cadherin increased both activation of IGF1R signaling and efficacy to anti-IGF1R/InsR therapies. PLA demonstrated a direct endogenous interaction between IGF1R and E-cadherin at points of cell-cell contact. Increased expression of IGF1 ligand and levels of IGF1R/InsR phosphorylation were observed in E-cadherin-deficient ER+ ILC compared with IDC tumors. IGF1R pathway inhibitors were effective in inhibiting growth in ER+ ILC cell lines and synergized with endocrine therapy and similarly IGF1R/InsR inhibition reduced proliferation in ILC tumor explant culture.Conclusions: We provide evidence that loss of E-cadherin hyperactivates the IGF1R pathway and increases sensitivity to IGF1R/InsR targeted therapy, thus identifying the IGF1R pathway as a potential novel target in E-cadherin-deficient breast cancers. Clin Cancer Res; 24(20); 5165-77. ©2018 AACR.

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