Abstract B158: Exploiting IGF1R pathway activation as a therapeutic strategy for E-cadherin deficient breast cancers
Authors: Nagle Alison M. , Erdem Cemal , Levine Kevin , Sotiriou Christos , Metzger Otto , Taylor D Lans , Lezon Timothy , Oesterreich Steffi , Lee Adrian V. 
Published: August 2018

Abstract
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; however, only a subset of patients show beneficial response to IGF1R inhibitors in clinical trials. To identify putative biomarkers of response to IGF1, we performed a proteomic screen in 21 breast cancer cell lines stimulated with IGF1. Using a novel integrated computational and experimental approach, we identified levels of E-cadherin (CDH1), a major component of the adherens junction (AJ), as a repressor of IGF1R signaling. CDH1 is genetically lost in invasive lobular breast cancer (ILC), a subtype of breast cancer that accounts for ~10-15% of total cases. E-cadherin is also downregulated in estrogen receptor (ER)-negative breast cancers that have undergone epithelial to mesenchymal transition. Consistent with the proteomic screen, knockdown of E-cadherin enhanced IGF1-induced activation of IGF1R and downstream Akt and ERK1/2 phosphorylation, and this enhanced cell cycle progression. Disruption of the AJ alone with an E-cadherin monoclonal antibody also enhanced IGF1R signaling. Further, we have shown a direct interaction of IGF1R and E-cadherin using in situ proximity ligation assay indicating a physical regulation of E-cadherin on IGF1R signaling. Supporting the clinical relevance of our observations, we found increased expression of IGF1 ligand and increased IGF1R phosphorylation in E-cadherin deficient ER+ ILC tumors in The Cancer Genome Atlas (TCGA) compared to ER+ invasive ductal carcinomas (IDC). We also discovered a correlation between mRNA expression and the activation of the IGF gene signature in (1) a cohort of ER+ ILC tumors compared to ER+ IDC and (2) a subset of ER-negative tumors within TCGA. We have previously published that IGF1R inhibitors are effective in inhibiting growth of ER-negative breast cancer cell lines and xenograft models in combination with chemotherapy. Thus, we focused our studies on understanding the utility of IGF1R pathway inhibition in ER+ ILC as a therapeutic strategy. Our data indicate that IGF1R and Akt pathway inhibitors are effective in inhibiting growth in ER+ ILC cell lines and ex vivo tumor culture, and synergize with standard-of-care anti-ER targeted therapy. Therefore, we hypothesize that loss of E-cadherin potentiates IGF1R 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.
Citation Format: Alison M. Nagle, Cemal Erdem, Kevin Levine, Christos Sotiriou, Otto Metzger, D Lans Taylor, Timothy Lezon, Steffi Oesterreich, Adrian V. Lee. Exploiting IGF1R pathway activation as a therapeutic strategy for E-cadherin deficient breast cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B158.