Loss of E-cadherin Enhances IGF1–IGF1R Pathway Activation and Sensitizes Breast Cancers to Anti-IGF1R/InsR Inhibitors
| Autor: | Alison M. Nagle, David N. Boone, Adrian V. Lee, Tiffany A. Katz, Britta M. Jacobsen, Nilgun Tasdemir, Kara Burlbaugh, Steffi Oesterreich, Julie A. Scott, Jennifer M. Atkinson, Kevin M. Levine, Justin W Kehm |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.medical_treatment Proximity ligation assay Receptor IGF Type 1 Targeted therapy CDH1 Mice 0302 clinical medicine Medicine Insulin-Like Growth Factor I RNA Small Interfering skin and connective tissue diseases biology Cell Cycle Drug Synergism Cadherins Immunohistochemistry Oncology 030220 oncology & carcinogenesis Female hormones hormone substitutes and hormone antagonists Signal Transduction endocrine system Antineoplastic Agents Breast Neoplasms Article 03 medical and health sciences Breast cancer Cell Line Tumor Animals Humans Cell Proliferation Insulin-like growth factor 1 receptor Dose-Response Relationship Drug business.industry Cadherin Gene Expression Profiling Cancer Receptors Somatomedin medicine.disease Xenograft Model Antitumor Assays body regions Disease Models Animal Insulin receptor 030104 developmental biology Drug Resistance Neoplasm Cancer research biology.protein business |
| Zdroj: | Clinical Cancer Research. 24:5165-5177 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-18-0279 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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