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E-Cadherin Loss and Other Drivers of Invasive Lobular Breast Carcinoma

Savariau, Laura (2023) E-Cadherin Loss and Other Drivers of Invasive Lobular Breast Carcinoma. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Invasive lobular carcinoma (ILC) is the second most frequently diagnosed histologic subtype of invasive breast cancer following no special type carcinoma (NST) and accounts for 10-15% of all cases. The pathognomonic hallmark of ILC is the genetic loss of E-cadherin (CDH1), causing the disruption of adherens junctions and resulting in linear growth of ILC cells. There is limited data on the role of E-cadherin in ILC metastasis. Therefore, I generated three ILC cell lines--MDA-MB-134-VI, SUM44PE, and BCK4--with inducible E-cadherin expression that successfully restored adherens junctions. E-cadherin expression significantly reduced growth in vitro, but did not affect primary tumor growth following injection in the mammary fat pad of immunocompromised mice. E-cadherin expression failed to increase the poor migratory and invasive ability of ILC cell lines, but it decreased haptotaxis to fibronectin and collagen I, while increasing adherence to the latter in SUM44PE only. Clinically, ILC tumors metastasize more frequently to the gastrointestinal tract and ovaries compared to NST tumors. E-cadherin expression reduced metastatic seeding in MDA-MB-134-VI and altered metastatic organotropism in both MDA-MB-134-VI and SUM44PE following injection in mice.
To further understand metastases in patients with ILC; 1) I performed transcriptomic analysis of primary tumors, brain and ovarian metastases from mice orthotopically injected with MDA-MB-134-VI. Genes involved in extracellular matrix remodeling in the primary tumor, and increased expression of the known brain metastasis driver RET in the brain metastases were identified.
2) I contributed to the characterization of the Calcium Sensing Receptor (CaSR) which was found upregulated in ovarian metastases in a cohort of paired primary breast tumor and ovarian metastases. I used CaSR over-expression ILC cell lines and observed that activation of CaSR with calcium promoted migration and increased quantity of F-actin per cell. Both phenotypes were mediated by the MEK/ERK signaling pathway, and the migratory phenotype required estrogen receptor activation.
Collectively, my work created and characterized novel cell line and xenograft models to improve our understanding of the hallmark loss of E-cadherin and other drivers of ILC, which will enable the development of more effective therapies and improve the outcome of patients with ILC.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Savariau, Lauralas344@pitt.edulas3440000-0003-0452-9481
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorOsterreich, Steffisto16@pitt.edusto16
Committee MemberUrban, Zsolturbanz@pitt.eduurbanz
Committee MemberRoman, Bethromanb@pitt.eduromanb
Committee MemberDiergaarde, Brendabbd3@pitt.edubbd3
Date: 3 January 2023
Date Type: Publication
Defense Date: 14 December 2022
Approval Date: 3 January 2023
Submission Date: 15 December 2022
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 167
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: NA
Date Deposited: 03 Jan 2023 15:17
Last Modified: 03 Jan 2023 15:17

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