Pubertal exposure to dietary advanced glycation end products disrupts ductal morphogenesis and induces atypical hyperplasia in the mammary gland.

BACKGROUND: Advanced glycation end products (AGEs) are reactive metabolites intrinsically linked with modern dietary patterns. Processed foods, and those high in sugar, protein and fat, often contain high levels of AGEs. Increased AGE levels are associated with increased breast cancer risk, however their significance has been largely overlooked due to a lack of direct cause-and-effect relationship. METHODS: To address this knowledge gap, FVB/n mice were fed regular, low AGE, and high AGE diets from 3 weeks of age and mammary glands harvested during puberty (7 weeks) or adulthood (12 weeks and 7 months) to determine the effects upon mammary gland development. At endpoint mammary glands were harvested and assessed histologically (n ≥ 4). Immunohistochemistry and immunofluorescence were used to assess cellular proliferation and stromal fibroblast and macrophage recruitment. The Kruskal-Wallis test were used to compare continuous outcomes among groups. Mammary epithelial cell migration and invasion in response to AGE-mediated fibroblast activation was determined in two-compartment co-culture models. In vitro experiments were performed in triplicate. The nonparametric Wilcoxon rank sum test was used to compare differences between groups. RESULTS: Histological analysis revealed the high AGE diet delayed ductal elongation, increased primary branching, as well as increased terminal end bud number and size. The high AGE diet also led to increased recruitment and proliferation of stromal cells to abnormal structures that persisted into adulthood. Atypical hyperplasia was observed in the high AGE fed mice. Ex vivo fibroblasts from mice fed dietary-AGEs retain an activated phenotype and promoted epithelial migration and invasion of non-transformed immortalized and tumor-derived mammary epithelial cells. Mechanistically, we found that the receptor for AGE (RAGE) is required for AGE-mediated increases in epithelial cell migration and invasion. CONCLUSIONS: We observed a disruption in mammary gland development when mice were fed a diet high in AGEs. Further, both epithelial and stromal cell populations were impacted by the high AGE diet in the mammary gland. Educational, interventional, and pharmacological strategies to reduce AGEs associated with diet may be viewed as novel disease preventive and/or therapeutic initiatives during puberty.

Pubertal mammary development as a "susceptibility window" for breast cancer disparity.

Factors such as socioeconomic status, age at menarche and childbearing patterns are components that have been shown to influence mammary gland development and establish breast cancer disparity. Pubertal mammary gland development is selected as the focus of this review, as it is identified as a "window of susceptibility" for breast cancer risk and disparity. Here we recognize non-Hispanic White, African American, and Asian American women as the focus of breast cancer disparity, in conjunction with diets associated with changes in breast cancer risk. Diets consisting of high fat, N-3 polyunsaturated fatty acids, N-6 polyunsaturated fatty acids, as well as obesity and the Western diet have shown to lead to changes in pubertal mammary gland development in mammalian models, therefore increasing the risk of breast cancer and breast cancer disparity. While limited intervention strategies are offered to adolescents to mitigate development changes and breast cancer risk, the prominent solution to closing the disparity among the selected population is to foster lifestyle changes that avoid the deleterious effects of unhealthy diets.