Pubertal exposure to dietary advanced glycation end products disrupts ductal morphogenesis and induces atypical hyperplasia in the mammary gland
Abstract 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,...
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BMC
2023-10-01
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Series: | Breast Cancer Research |
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Online Access: | https://doi.org/10.1186/s13058-023-01714-4 |
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author | Bradley A. Krisanits Reid Schuster Jaime Randise Lourdes M. Nogueira Jackson T. Lane Gowtami A. Panguluri Hong Li Kristi Helke Maria C. Cuitiño Christopher Koivisto Laura Spruill Michael C. Ostrowski Steven M. Anderson David P. Turner Victoria J. Findlay |
author_facet | Bradley A. Krisanits Reid Schuster Jaime Randise Lourdes M. Nogueira Jackson T. Lane Gowtami A. Panguluri Hong Li Kristi Helke Maria C. Cuitiño Christopher Koivisto Laura Spruill Michael C. Ostrowski Steven M. Anderson David P. Turner Victoria J. Findlay |
author_sort | Bradley A. Krisanits |
collection | DOAJ |
description | Abstract 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. |
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institution | Directory Open Access Journal |
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language | English |
last_indexed | 2024-03-09T14:47:58Z |
publishDate | 2023-10-01 |
publisher | BMC |
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series | Breast Cancer Research |
spelling | doaj.art-0337fd19f5054494afdb0a79e61992ea2023-11-26T14:37:42ZengBMCBreast Cancer Research1465-542X2023-10-0125111710.1186/s13058-023-01714-4Pubertal exposure to dietary advanced glycation end products disrupts ductal morphogenesis and induces atypical hyperplasia in the mammary glandBradley A. Krisanits0Reid Schuster1Jaime Randise2Lourdes M. Nogueira3Jackson T. Lane4Gowtami A. Panguluri5Hong Li6Kristi Helke7Maria C. Cuitiño8Christopher Koivisto9Laura Spruill10Michael C. Ostrowski11Steven M. Anderson12David P. Turner13Victoria J. Findlay14Department of Pathology and Laboratory Medicine, Medical University of South CarolinaDepartment of Pathology and Laboratory Medicine, Medical University of South CarolinaDepartment of Pathology and Laboratory Medicine, Medical University of South CarolinaDepartment of Pathology and Laboratory Medicine, Medical University of South CarolinaDepartment of Surgery and Massey Cancer Center, Virginia Commonwealth UniversityDepartment of Surgery and Massey Cancer Center, Virginia Commonwealth UniversityDepartment of Public Health Sciences, Medical University of South CarolinaDepartment of Pathology and Laboratory Medicine, Medical University of South CarolinaDepartment of Biochemistry and Molecular Biology, Medical University of South CarolinaDepartment of Biochemistry and Molecular Biology, Medical University of South CarolinaDepartment of Pathology and Laboratory Medicine, Medical University of South CarolinaDepartment of Biochemistry and Molecular Biology, Medical University of South CarolinaDepartment of Pathology, University of Colorado Anschutz Medical CampusDepartment of Pathology and Laboratory Medicine, Medical University of South CarolinaDepartment of Pathology and Laboratory Medicine, Medical University of South CarolinaAbstract 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.https://doi.org/10.1186/s13058-023-01714-4Advanced glycation end productsRAGEMammary gland developmentPubertyDietMicroenvironment |
spellingShingle | Bradley A. Krisanits Reid Schuster Jaime Randise Lourdes M. Nogueira Jackson T. Lane Gowtami A. Panguluri Hong Li Kristi Helke Maria C. Cuitiño Christopher Koivisto Laura Spruill Michael C. Ostrowski Steven M. Anderson David P. Turner Victoria J. Findlay Pubertal exposure to dietary advanced glycation end products disrupts ductal morphogenesis and induces atypical hyperplasia in the mammary gland Breast Cancer Research Advanced glycation end products RAGE Mammary gland development Puberty Diet Microenvironment |
title | Pubertal exposure to dietary advanced glycation end products disrupts ductal morphogenesis and induces atypical hyperplasia in the mammary gland |
title_full | Pubertal exposure to dietary advanced glycation end products disrupts ductal morphogenesis and induces atypical hyperplasia in the mammary gland |
title_fullStr | Pubertal exposure to dietary advanced glycation end products disrupts ductal morphogenesis and induces atypical hyperplasia in the mammary gland |
title_full_unstemmed | Pubertal exposure to dietary advanced glycation end products disrupts ductal morphogenesis and induces atypical hyperplasia in the mammary gland |
title_short | Pubertal exposure to dietary advanced glycation end products disrupts ductal morphogenesis and induces atypical hyperplasia in the mammary gland |
title_sort | pubertal exposure to dietary advanced glycation end products disrupts ductal morphogenesis and induces atypical hyperplasia in the mammary gland |
topic | Advanced glycation end products RAGE Mammary gland development Puberty Diet Microenvironment |
url | https://doi.org/10.1186/s13058-023-01714-4 |
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