Date of Award

2020

Embargo Period

1-1-2025

Document Type

Thesis - MUSC Only

Degree Name

Master of Biomedical Science

Department

Pathology

College

College of Graduate Studies

First Advisor

Victoria Findlay

Second Advisor

David Turner

Third Advisor

Amy Bradshaw

Fourth Advisor

Kristi Helke

Abstract

Evidence suggests that lifestyle and dysregulations during various windows of susceptibility in breast development increases cancer risk. Advanced glycation end products (AGEs) are reactive metabolites produced through the Maillard reaction and direct oxidation of biological macromolecules. Here, we examined the impact of food-derived (dietary) AGEs on fibroblasts within the pubertal mammary gland and whether the resultant fibroblasts exhibit an ‘activated’ phenotype and subsequently influence epithelial cell migration and/or invasion. Primary fibroblasts were isolated from the mammary glands of high-AGE diet fed mice at 7 weeks of age. We demonstrated a transcriptional increase in fibroblast activation markers and the Receptor of AGE (RAGE) in the primary and TERT immortalized fibroblasts over multiple passages in culture. We demonstrate that high AGE exposed fibroblasts increased migration of both normal and transformed mammary epithelial cells. Treatment of fibroblasts with AGE ex vivo results in an additional increase in epithelial cell migration. We made similar observations with invasion assays, whereby high AGE fibroblasts were able to increase the invasion of transformed mammary epithelial cells, with a further increase observed after ex vivo AGE treatment. Using primary fibroblasts isolated from a novel RAGE null (-/-) mouse model, we demonstrate that the AGE-mediated increase in migration and invasion was RAGE-dependent. These data together imply that dietary-AGEs cause a fibroblast ‘activated’ phenotype in vivo that is sustained ex vivo. This AGE:RAGE signaling axis represents a potential response to early life AGE exposure and may influence fibroblast-epithelial cellular interactions in the pubertal mammary gland which has the potential to increase breast cancer risk.

Rights

All rights reserved. Copyright is held by the author.

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