Date of Award

1-1-2018

Embargo Period

1-1-2021

Document Type

Thesis

Department

Pathology and Laboratory Medicine

College

College of Graduate Studies

First Advisor

David P. Turner

Second Advisor

Victoria J. Findlay

Third Advisor

Kristi L. Helke

Fourth Advisor

Philip H. Howe

Abstract

The mammary gland continues to develop postnatally through puberty, pregnancy, lactation and involution. Evidence supports the notion that critical events in mammary development permanently alter developmentally regulated programs which influence the breast microenvironment to increase breast cancer risk. Advanced glycation end-products (AGEs) are highly reactive metabolites that irreversibly accumulate in tissues as we grow older. The pathogenic effects of AGEs include tissue degeneration, protein dysfunction, aberrant cell signaling and reduced genetic fidelity. AGE accumulation can contribute to pro-inflammatory and -oxidant phenotypes when signaling through the receptor for advanced glycation end-products. AGEs form during normal metabolism but critically, lifestyle factors such as poor diet, a sedentary lifestyle and being obese also contribute to the AGE accumulation pool. Previous work performed in our lab with mice fed a high AGE diet showed a significant dysregulation of mammary gland development and the formation of hyperproliferative structures. In this study, we further characterized the AGE induced hyperproliferative structures and made an initial assessment of their ability to confer metabolic memory using diet intervention strategies. Given the AGE induced effects on mammary development during puberty, we also examined the effects of chronic AGE consumption on the mammary gland during pregnancy and offspring. In summary, increased AGE consumption during pubertal growth and mammary development during pregnancy results in significant disruption of normal mammary development. Chronic consumption of a diet high in AGEs leads to disruption of the mammary gland microenvironment, thereby posing an increased risk of developing breast cancer later in life, particularly in susceptible populations.

Rights

All rights reserved. Copyright is held by the author.

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