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INVESTIGATING THE INFLUENCE OF OXIDATIVE STRESS AND THE ROLE OF PRDX1 IN THE REGULATION OF LYSYL OXIDASE MEDIATED ECM AND COLLAGEN REMODELING IN BREAST CANCER METASTASIS

Attaran, Shireen (2019) INVESTIGATING THE INFLUENCE OF OXIDATIVE STRESS AND THE ROLE OF PRDX1 IN THE REGULATION OF LYSYL OXIDASE MEDIATED ECM AND COLLAGEN REMODELING IN BREAST CANCER METASTASIS. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Breast cancer progression and metastasis includes not only cell-autonomous properties of cancer epithelial cells, but also the influence of the neighboring tumor stromal cells. In breast cancer, almost 80% of stromal associated fibroblasts (SAFs) acquire a cancer associated fibroblast (CAF)-like “activated phenotype”. This CAF activated phenotype is associated with elevated levels of reactive oxygen species (ROS) that are linked with tumor remodeling and spreading. Members of the lysyl oxidase (LOX) family of enzymes participate in tumor remodeling through the promotion of collagen crosslinking and collagen fibril production. We hypothesize that stromal Prdx1 regulates ROS dependent metastasis/migration of cancer cells through effects on LOX activity. Our preliminary data reveal that Prdx1 prevents CAF-induced malignant phenotypes in breast cancer (epithelial) cells in an H2O2-dependent manner. When compared to wild-type mice, Prdx1-/- SAFs show a marked increase in CAF-specific characteristics, including increased expression of CAF-specific markers, motility and invasiveness of SAFs and SAF-induced chemotactic migration and invasion by breast cancer epithelial cells in vitro. Lack of Prdx1 in mammary SAFs results in the upregulation of markers of the activated phenotype, such as collagen, vimentin and α-SMA leading to an increase in co-migration and invasion. As shPrdx1 SAFs show CAF-like mesenchymal properties in vitro, we tested in vivo if Prdx1 suppresses migration of breast cancer cells by generating a syngeneic mouse model to image BALB/c derived SAFs shPrdx1/SAFs pLKO1 (expressing iRFP). Immunoprecipitation data suggests that Prdx1 associates with LOX family proteins. Moreover, Prdx1-deficient SAFs displayed elevated LOX secretion into the ECM compared to Prdx1-proficient SAFs. Lastly, of translational relevance, we have shown that SAF Prdx1 becomes inactivated by cancer cells through phosphorylation of Y194 Prdx1. The peroxidase, Prdx1, is a regulator of LOX and CAF activity and SAFs lacking Prdx1 may serve as a valuable model system to investigate the biology of CAFs in vitro and in vivo.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Attaran, Shireensha60@pitt.edu
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairPagano, Patrickpagano@pitt.edu
Thesis Advisorneumann, carolacan44@pitt.edu
Committee Memberdavidson, lancelad43@pitt.edu
Committee Memberromero, guillermoggr@pitt.edu
Committee Memberhuang, yiyih26@pitt.edu
Date: 8 February 2019
Date Type: Publication
Defense Date: 17 September 2018
Approval Date: 8 February 2019
Submission Date: 28 January 2019
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 104
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: breast cancer
Date Deposited: 08 Feb 2019 21:57
Last Modified: 08 Feb 2019 21:57
URI: http://d-scholarship.pitt.edu/id/eprint/35937

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