Abstract 1880: Determining the role of E-cadherin in regulating IGF1 signaling in breast cancer: An interaction predicted by large-scale modeling
Authors: Nagle Alison M. , Erdem Cemal , Wang YuFen , Levine Kevin , Katz Tiffany , Taylor D. Lansing , Lee Adrian V. , Lezon Timothy R. 
Published: July 2016

Insulin-like growth factor I (IGF1) plays an important role in breast cancer initiation and progression due to its regulation of cell proliferation, migration, and invasion. These characteristics make IGF1R an attractive therapeutic target. While numerous clinical trials have sought to inhibit IGF1R action, these were largely unsuccessful due to a lack of biomarkers for positive therapeutic response, poor patient selection, and potential compensatory signaling by the highly similar insulin receptor (InsR). To identify biomarkers of response, our laboratory identified a set of genes regulated by IGF1 (IGF-sig) that revealed a correlation between activation of the IGF-sig and poor prognosis in estrogen receptor (ER)-negative breast cancer. Further, we showed that ER-negative breast cancer cells are sensitive to IGF1R inhibition both in vitro and in vivo. In an effort to better understand the IGF1 and insulin signaling networks in breast cancer, we performed a reverse phase protein array (RPPA) using 134 antibodies on lysates from twenty-one breast cancer cell lines stimulated with a six point time-course of IGF1 or insulin. We developed a time-dependent model to predict differential mediators of IGF1 and insulin signaling using perturbation analysis. The model predicted that alterations in levels of E-cadherin (CDH1), a major component of the adherens junction, affect IGF1 induced Akt activation. In breast cancer, E-cadherin is genetically lost in invasive lobular cancer (ILC), a subtype that accounts for ∼10-15% of breast cancers. Alternatively, invasive ductal cancers may lose E-cadherin via EMT. I confirmed this in silico prediction, showing that shRNA reduction of E-cadherin enhances the ability of IGF1 to induce Akt signaling, and additionally IGF1R, ERK and S6 ribosomal protein activation. Supporting the clinical relevance of our observations, we found a correlation between loss of E-cadherin (CDH1) mRNA expression and the activation of the IGF-sig in ER-negative tumors within The Cancer Genome Atlas (TCGA). Therefore, we hypothesize that loss of E-cadherin potentiates IGF1 signaling to enhance breast cancer progression, and that loss of E-cadherin expression in ILC and ER-negative tumors may highlight those susceptible to IGF1R inhibition. These studies will investigate how E-cadherin modulates IGF1 signaling and the interaction with EMT with the goal of better defining breast cancers that may respond to IGF1R inhibitors.

Citation Format: Alison M. Nagle, Cemal Erdem, YuFen Wang, Kevin Levine, Tiffany Katz, D. Lansing Taylor, Adrian V. Lee, Timothy R. Lezon. Determining the role of E-cadherin in regulating IGF1 signaling in breast cancer: An interaction predicted by large-scale modeling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1880.