Loss of E-cadherin enhances IGF1-IGF1R pathway activation and sensitizes breast cancers to anti-IGF1R inhibitors
| Autor: | David N. Boone, Nilgun Tasdemir, Adrian V. Lee, Alison M. Nagle, Tiffany A. Katz, Kara Burlbaugh, Justin W Kehm, Julie A. Scott, Britta M. Jacobsen, Steffi Oesterreich, Jennifer M. Atkinson, Kevin M. Levine |
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| Rok vydání: | 2018 |
| Předmět: |
0303 health sciences
biology business.industry medicine.medical_treatment Estrogen receptor Cancer Proximity ligation assay medicine.disease 3. Good health Targeted therapy CDH1 body regions 03 medical and health sciences 0302 clinical medicine Breast cancer 030220 oncology & carcinogenesis Invasive lobular carcinoma medicine Cancer research biology.protein skin and connective tissue diseases business 030304 developmental biology Insulin-like growth factor 1 receptor |
| DOI: | 10.1101/253278 |
| Popis: | PurposeInsulin-like growth factor I (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 therapies in breast cancer.Experimental DesignBreast cancer cell lines were used to assess how altered E-cadherin levels regulate IGF1R signaling and response to two anti-IGF1R therapies. In situ proximity ligation assay (PLA) was used to define interaction between IGF1R and E-cadherin. TCGA RNA-seq and RPPA data was used to compare IGF1R 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.ResultsDiminished functional E-cadherin increased both activation of IGF1R signaling and efficacy to anti-IGF1R 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 phosphorylation were observed in E-cadherin deficient ER+ ILC compared to IDC tumors. IGF1R pathway inhibitors were effective in inhibiting growth in ER+ ILC cell lines and synergized with endocrine therapy and similarly IGF1R inhibition reduced proliferation in ILC tumor explant culture.ConclusionsWe provide evidence that loss of E-cadherin hyperactivates the IGF1R pathway and increases sensitivity to IGF1R targeted therapy, thus identifying the IGF1R pathway as a potential novel target in E-cadherin deficient breast cancers.STATEMENT OF SIGNIFICANCEIGF1R signaling is an attractive therapeutic target in breast cancer due to its regulation of proliferation, migration, and invasion. However, clinical trials targeting IGF1R have largely been unsuccessful due to lack of biomarkers to stratify patients for therapeutic response. In this study, we demonstrate loss of E-cadherin as a potential biomarker for response to anti-IGF1R therapy, and show efficacy of IGF1R inhibition in ER+ ILC in combination with endocrine therapy. Patients with ER+ ILC have poorer long-term outcomes than patients with ER+ IDC and have a propensity for increased late recurrences, highlighting the need for improved therapeutic strategies for this subtype of breast cancer. Here, we credential IGF1R inhibition as a novel therapeutic strategy in combination with endocrine therapy for the treatment of ER+ ILC. |
| Databáze: | OpenAIRE |
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