Abstract 2234: Dietary-AGE ingestion during puberty modifies the breast microenvironment to alter mammary gland development: Linking diet, development and breast cancer risk

Evidence supports the notion that critical events during mammary development permanently alter developmentally regulated programs which influence the breast microenvironment to increase breast cancer risk. This is analogous to metabolic memory in diabetic patients where early metabolic events have been found to be remembered and affect disease severity later in life. Advanced glycation end products (AGEs) are highly reactive metabolites that irreversibly accumulate in tissues as we age. AGE accumulation can contribute to pro-inflammatory and -oxidant phenotypes when signaling through the receptor for advanced glycation end products (RAGE). The pathogenic effects of AGE-RAGE signaling include tissue degeneration, protein dysfunction, aberrant cell signaling, and reduced genetic fidelity. 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. The permanence of AGE adducts and their ability to mediate chronic and persistent inflammatory and oxidative stresses is particularly compatible to the concept of metabolic memory. Our dietary studies in pubertal FVB/n mice fed a high AGE diet show a significant dysregulation of mammary gland development and hyperplastic lesion formation. We observe delayed mammary ductal extension, increased ductal branching and aberrant terminal end-bud (TEB) morphology. The basal myoepithelial cell layer surrounding mammary ducts and TEBs was irregular and epithelial cell proliferation was increased. Molecular characterization of these hyperplastic lesions were defined using DCIS progression markers by histopathological staining and qRT-PCR. Elevated AGE levels accompanied increased RAGE expression and increased macrophage and fibroblast infiltration around the TEBs. In attempt to reverse the effects caused by a high AGE diet, mice were fed a control diet after a pubertal high AGE diet. Hyperplastic lesions persisted despite diet intervention. Importantly, hyperplastic lesions were not observed in mice fed a control diet during puberty, then switched to a high AGE diet. These data indicate that exposure to AGE induced changes during puberty may leave a long-lasting imprint analogous to metabolic memory. In conclusion, increased AGE consumption during pubertal growth results in significant disruption of normal mammary development and the appearance of hyperplastic lesions by adulthood. Consumption of a high AGE diet despite a control diet intervention, reveals hyperplastic lesions indicative of metabolic memory. We hypothesize that the high AGE diet may leave a metabolic imprint on the mammary gland microenvironment, increasing the risk of future breast cancer development. Citation Format: Jaime F. Randise, Bradley A. Krisanits, Lourdes M. Nogueira, Kristi L. Helke, Taaliah Campbell, Victoria J. Findlay, David P. Turner. Dietary-AGE ingestion during puberty modifies the breast microenvironment to alter mammary gland development: Linking diet, development and breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2234.