Abstract C025: Dietary-AGE ingestion during puberty modifies the breast microenvironment to alter mammary gland development: Linking lifestyle with cancer disparity

Abstract

Advanced glycation end products (AGEs) are highly reactive metabolites that irreversibly accumulate in tissues as we grow older. Accumulation of AGEs in the body can contribute to proinflammatory and pro-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 are formed 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 permanent nature of AGE adducts and their ability to mediate chronic and persistent inflammatory and oxidative stresses is particularly compatible with the concept of metabolic memory. Our dietary studies in pubertal FVB/n mice after chronic consumption of AGE show a significant dysregulation of mammary gland development and the formation of hyperplastic lesions. 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 was defined by using markers of DCIS progression by histopathologic staining and qRT-PCR. Elevated AGE levels were accompanied by increased expression of RAGE and increased immune (macrophage) and stromal (fibroblast) infiltration around the TEBs. In an 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 after. These data not only illustrate the importance of the pubertal window in the mediation of lifestyle factors but also indicate that exposure to AGE-induced changes during puberty may leave a long-lasting imprint analogous to the concept of metabolic memory. Additionally, in our feasibility studies, both pharmacologic (NCT02946996; NCT03092635) and interventional (NCT03459755) strategies were shown to reduce circulating AGE levels in cancer survivors. Based on associations between diet, lifestyle, and race, increases in AGE accumulation may represent a novel biologic mechanism contributing to cancer disparity and may represent a new paradigm contributing to the increased cancer incidence and mortality figures observed within health-disparity populations. Given the potential benefits of lifestyle changes and the potential biologic role of AGEs in promoting cancer, opportunities exist for collaborations impacting basic, translational, epidemiologic and cancer prevention initiatives. Citation Format: Bradley A. Krisanits, Jaime F. Randise, Lourdes M. Nogueira, Kristi Helke, Michael C. Ostrowski, Katie Theis, Maria Cuitino, Gayenel Magwood, Marvella E. Ford, Victoria J. Findlay, David P. Turner. Dietary-AGE ingestion during puberty modifies the breast microenvironment to alter mammary gland development: Linking lifestyle with cancer disparity [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C025.