Date of Award

2017

Document Type

Thesis

Degree Name

Master of Biomedical Science

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

Elizabeth Yeh

Fifth Advisor

Robin C. Muise-Helmericks

Abstract

The mammary gland is one of few organs that continues to develop postnatally, through puberty, pregnancy, lactation and involution. Interestingly, these times of development are also considered windows of susceptibility for future development of breast cancer. Studies have shown that processes important in mammary gland development are often deregulated during breast cancer tumorigenesis. Advanced glycation end products (AGEs) are highly reactive metabolites produced during normal metabolism. AGE content in the Western Diet has consistently increased over the years and accumulation of AGEs in the body leads to pro- inflammatory and pro-oxidant effects. Diet, including a diet high in fat has been shown to deregulate mammary development and lead to increased breast cancer risk. This study examines the impact of a diet high in AGEs on pubertal mammary gland development in mice. Mice were fed a control and high AGE diet from onset of puberty (3 weeks) to experimental endpoints of 7, 8 (pubertal) and 12 weeks (adulthood). At each experimental endpoint blood was collected for analysis of circulating AGEs and mammary gland tissue was collected for whole mounting, immunohistochemistry of AGE, RAGE, Ki67, αSMA, and F4/80 as well as morphology with hematoxylin and eosin (H&E). Mice fed the high AGE diet showed increase ductal branching, terminal end bud (TEB) number and size, as well as a delay of ductal extension. Immunohistochemistry techniques showed increased proliferation (Ki67) and disruption of myoepithelial layer (αSMA) in mice fed a high AGE diet. Histology revealed changes in morphology of gland structures, increased recruitment of stromal cells surrounding ductal/TEB structures, including macrophages and activated fibroblasts, as well as the formation of pre- neoplastic like lesions in adulthood with mice fed a high and low AGE diet. In summary, we observed a significant disruption of normal pubertal mammary gland development in mice fed a high AGE diet when compared to mice fed a control diet, possibly leading to increased breast cancer risk in adulthood.

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