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Loss of E-cadherin Activates a Targetable IGF1R Pathway in Invasive Lobular Breast Carcinoma

Elangovan, Ashuvinee (2022) Loss of E-cadherin Activates a Targetable IGF1R Pathway in Invasive Lobular Breast Carcinoma. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Invasive Ductal Carcinoma (IDC) and Invasive Lobular Carcinoma (ILC) are two major subtypes of breast cancer with significant differences in their histological and molecular underpinnings. ILC has a unique hallmark of loss of E-cadherin (CDH1) in 90% of the cases, which we have previously demonstrated as a negative regulator of Insulin-like Growth Factor 1 (IGF1) receptor, IGF1R through a comprehensive analysis of cell line models and tumor samples on TCGA. We propose that the loss of E-cadherin in ILC sensitizes cells to growth factor signaling and thus alters their susceptibility to growth factor signaling inhibition. We generated CDH1 knockout (KO) IDC cell lines to investigate the mechanism by which E-cadherin loss activates IGF pathway and its subsequent effectors while also assessing its targetability in patients. CDH1 KO cells exhibited anchorage independent growth in suspension culture and altered p120 catenin localization as seen in ILC cells. Through in vitro studies, we observed increased signaling sensitivity to IGF/ insulin ligands where the high activation levels are sustained for an extended duration in the KO cells. In addition, there was higher migratory potential in the CDH1 KO cells, which was further enhanced as a chemotactic response to IGF1 or serum and as a haptotactic response to Collagen I. This phenotype was reversed with an IGF1R inhibitor to exhibit phenotype specificity. Despite no consistent differences in membranous IGF1R levels, higher ligand-receptor interaction was observed with E-cadherin loss. Our results currently demonstrate IGF1R’s increased availability for ligand binding which in turn allows for an enhanced signaling activation. As an extension to the pathway activation, increased susceptibility to IGF1R, PI3K, AKT and MEK inhibitors was also observed in T47D CDH1 KO cells. With about 90% of ILC cases being ER+, we investigated and showed the additive effect of Fulvestrant with Akt inhibitors in KO cells. Although a clear susceptibility to Akt inhibitor was not seen in ILC patient-derived organoids (PDO), a favorable trend was observed when compared to IDC PDOs. Our findings elucidated IGF1 signaling repression by E-cadherin in ILC, thus supporting the use of E-cadherin loss as a stratification method for improved targeted therapy approaches.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Elangovan, Ashuvineease25@pitt.eduase250000-0001-5113-0970
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairGalbiati,
Thesis AdvisorLee, Adrian
Thesis AdvisorOesterreich,
Committee MemberSmithgall, Thomas
Committee MemberStabile, Laura
Committee MemberBrodsky, Jeffrey
Date: 15 June 2022
Date Type: Publication
Defense Date: 24 March 2022
Approval Date: 15 June 2022
Submission Date: 5 April 2022
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 182
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Genetics and Developmental Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Invasive Lobular carcinoma, E-cadherin, IGF1R, receptor availability
Date Deposited: 15 Jun 2022 14:40
Last Modified: 15 Jun 2022 14:40

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