Nagle, Alison
(2018)
Credentialing IGF1R pathway activation as a novel therapeutic target in E-cadherin deficient breast cancer.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Insulin-like growth factor 1 (IGF1) plays an important role in breast cancer initiation and progression due to its regulation of cell proliferation, migration, and invasion. Our laboratory previously demonstrated that overexpression of constitutively activated IGF1 receptor (IGF1R) transformed human mammary epithelial cells and induced epithelial to mesenchymal transition. These characteristics make IGF1R an attractive therapeutic target, however, only subsets of patients have shown beneficial response to anti-IGF1R therapy in clinical trials, likely due to crosstalk with the insulin signaling pathway and lack of predictive biomarkers. To identify biomarkers of response to activated IGF1 and insulin signaling, we performed a proteomic screen in 21 breast cancer cell lines stimulated with IGF1 and insulin. We identified E-cadherin (CDH1), a major component of the adherens junction, as a repressor of IGF1 and insulin signaling. We further provide evidence that loss of E-cadherin hyperactivates the IGF1R pathway and increases sensitivity to IGF1R targeted therapy, thus highlighting the IGF1R pathway as a potential target in E-cadherin deficient breast cancer. Knockdown or antibody-mediated inhibition of E-cadherin increased IGF1-induced activation of IGF1R signaling and cell cycle progression. IGF1R and E-cadherin co-localized at points of cell-cell contact and a direct endogenous interaction using in situ proximity ligation assay indicated a physical regulation of E-cadherin on IGF1R signaling. Importantly, the E-cadherin gene (CDH1) is genetically lost in invasive lobular breast carcinoma (ILC), a subtype of breast cancer accounting for ~10-15% of total cases. We found increased expression of IGF1 ligand and levels of IGF1R phosphorylation in E-cadherin deficient estrogen receptor positive (ER+) ILC in TCGA compared to ER+ invasive ductal carcinomas (IDC). We demonstrated that IGF1R and PI3K/Akt pathway inhibitors were effective in inhibiting growth in ER+ ILC cell lines and synergized with endocrine therapy. Additionally, we showed efficacy of IGF1R inhibition in ILC xenografts cultured ex vivo. Our data supports the use of IGF1R pathway inhibition as a potential novel therapeutic strategy for the treatment of ILC.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
26 March 2018 |
| Date Type: |
Publication |
| Defense Date: |
14 March 2018 |
| Approval Date: |
26 March 2018 |
| Submission Date: |
20 March 2018 |
| Access Restriction: |
3 year -- Restrict access to University of Pittsburgh for a period of 3 years. |
| Number of Pages: |
138 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Pharmacology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
insulin-like growth factor receptor
breast cancer
E-cadherin
invasive lobular carcinoma |
| Date Deposited: |
26 Mar 2018 13:12 |
| Last Modified: |
26 Mar 2021 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/33904 |
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