Lifestyle associated reactive metabolites and their negative impact on breast cancer risk

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PROJECT SUMMARY/ABSTRACT The focus of this study is on early life factors and their effect on mammary development during puberty and how they relate to increased breast cancer risk. At this time we do not understand what biological changes occur during pubertal mammary development which leads to a greater risk of developing cancer in later life. Identifying the molecular mechanisms that cause aberrant pubertal mammary development may lead to defined strategies to reduce breast cancer burden in later life. As our bodies use the sugars that we consume for energy they generate waste chemicals known as metabolites. One such group of metabolites is known as advanced glycation end products or AGEs for short. Critically apart from their production as a result of the breakdown of sugar, AGE’s are also formed through the ingestion of food and by external environmental factors such as lack of exercise. Changes in this dynamic equilibrium causes protein dysfunction, protein crosslinking, decreased genetic fidelity, altered gene expression profiles and aberrant cell signaling. Our studies have identified in animal models that a diet high in AGEs significantly alters how the breast develops during puberty. The tumor microenvironment is now becoming recognized as having a major role in facilitating both mammary development and cancer progression, and that, alterations in stromal cell signaling can precede epithelial cell alterations and act as drivers of the tumorigenic process. Critically, the high AGE diet produces architecture in the breast that resembles pre-neoplastic lesions with hyper-proliferative structures and increased levels of stromal cells. We also show that AGE levels are significantly elevated in the circulation and tumor tissue of breast cancer patients and that AGE treatment alters cancer associated signaling pathways to promote breast tumor growth. This study aims to define the mechanism by which a high-AGE diet causes the dysregulation of the mammary gland during puberty (SA1) and adulthood (SA2) and will ask if the changes observed lead to a higher risk of breast tumor formation and growth (SA3). A greater mechanistic understanding of the link between AGE intake during puberty and increased breast cancer risk may define novel potential strategies for lifestyle and pharmacological intervention aimed at reducing breast cancer risk at a defined window of susceptibility.