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Credentialing IGF1R pathway activation as a novel therapeutic target in E-cadherin deficient breast cancer

Nagle, Alison (2018) Credentialing IGF1R pathway activation as a novel therapeutic target in E-cadherin deficient breast cancer. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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:
CreatorsEmailPitt UsernameORCID
Nagle, Alisonamn66@pitt.eduamn66
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMonga, Satdarshansmonga@pitt.edusmonga
Thesis AdvisorLee, Adrianleeav@upmc.eduavl10
Committee MemberOesterreich, Steffioesterreichs@upmc.edusto16
Committee MemberSingh, Shivendrasinghs@upmc.edusvs2
Committee MemberJankowitz, Racheljankowitzr@upmc.edurcj8
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 2018 13:12
URI: http://d-scholarship.pitt.edu/id/eprint/33904

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