Abstract P4-05-01: Diet, development and predisposition to breast cancer: The impact of sugar derived metabolites (AGEs) on pubertal mammary gland development

Abstract

Abstract The mammary gland is one of the few organs that continues to develop postnatally through stages including puberty, pregnancy, lactation, and involution. The gland is composed of epithelial and stromal cells that include fibroblasts, adipocytes, endothelial cells, nerve cells, and macrophages. Terminal end bud (TEB) structures are found exclusively in the pubertal developmental stage. The formation of TEBs and side branching drives mammary gland epithelial cell invasion into the mammary fat pad, continuing until the entire fat pad is filled. Pubertal mammary gland morphogenesis integrates a balance of epithelial cell proliferation, differentiation, and apoptosis. Several studies have shown that the interaction between mammary epithelial and stromal cells is crucial for the proper postnatal development of the mammary ductal tree. Interestingly, studies have shown that processes important in mammary gland development are often deregulated during breast cancer tumorigenesis. Thus, understanding the complex signaling network as well as the interactions between the different cell types during mammary gland development will be vital for elucidating the mechanisms underlying breast cancer progression and metastasis. Glycation is the non-enzymatic glycosylation of sugar moieties to biological macromolecules such as protein and DNA which produces reactive metabolites known as advanced glycation end products (AGE's). AGE content in the Western Diet has consistently increased over the last 50 years due to increased consumption of sugar laden and cheap processed/manufactured foods which are high in reactive AGE metabolites. AGE containing food can lead to the accumulation of AGEs in the body overtime leading to pro-inflammatory and pro-oxidant effects when signaling through receptor for advanced glycation end products (RAGE). Leading too many complications associated with diseases including diabetes, Alzheimer's, heart disease and cancer. Preliminary data in our lab has shown that AGEs also have an effect on phosphorylation and signaling of estrogen receptor α (ERα), a key receptor and signaling pathway in the regulation of mammary gland development during puberty. This observation, together with the links between diet, mammary gland development and immune cell recruitment lead us to examine the biological effects of a diet high in AGEs on pubertal mammary gland development in mice. 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. Mice fed the high AGE diet showed increases in TEB number as well as width, length and area. We also observed an increase in ductal branching and a decrease in ductal extension. Future studies will assess the role of macrophage recruitment to the developing gland, specifically around the TEBs based on its reported role in normal TEB function. We also plan to assess ERa signaling in mice fed the high AGE diet based on the reported role of estrogen signaling in ductal elongation. Citation Format: Krisanits BA, Nogueira LM, Findlay VJ, Turner DP. Diet, development and predisposition to breast cancer: The impact of sugar derived metabolites (AGEs) on pubertal mammary gland development [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-05-01.