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

生活方式相关的反应性代谢物及其对乳腺癌风险的负面影响

基本信息

批准号：
10206074
负责人：
STEVEN M ANDERSON
金额：
$ 41.14万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10206074
关键词：
Adult Advanced Glycosylation End Products Alcohol consumption Animal Model Architecture Atypical hyperplasia Biological Blood Circulation Breast Breast Cancer Patient Breast Cancer Risk Factor Cancer Burden Carcinogens Cells Chemicals Chronic Consumption Cues Data Dependence Development Diet Dietary Intervention Disease Duct (organ) structure Elderly Environmental Risk Factor Epithelial Cells Equilibrium Estrogen Receptors Event Exercise Exposure to Fibroblasts Food Functional disorder Future Gene Expression Genetic Genetic Transcription Goals Growth Immune Inflammatory Ingestion Intake Intervention Intraepithelial Neoplasia Knock-out Lead Lesion Life Life Style Ligands Link Lymphoid Malignant Neoplasms Mammary Duct Mammary Neoplasms Mammary gland Mediating Metabolism Modeling Molecular Morphology Mus Myelogenous Nature Neoplasms Obesity Oncogenic Oxidative Stress Paracrine Communication Pharmacology Play Postmenopause Predisposition Process Production Proteins Proto-Oncogene Proteins c-akt Puberty Publishing Risk Role STAT3 gene Signal Pathway Signal Transduction Smoking Stress Stromal Cells Structure Testing Time Tissues Trees Tumor Tissue Unhealthy Diet Woman adduct advanced breast cancer breast cancer progression dietary early life exposure glucose metabolism high risk in vivo inflammatory milieu lifestyle factors macrophage malignant breast neoplasm mammary mammary epithelium mammary gland development mouse model neoplastic novel programs protein crosslink receptor for advanced glycation endproducts recruit sedentary sedentary lifestyle sugar tumor tumor growth tumor initiation tumor microenvironment tumor progression tumorigenic wasting

项目摘要

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.

项目概要/摘要本研究的重点是早期生活因素及其对青春期和乳腺发育的影响。它们与乳腺癌风险增加有何关系目前我们还不了解哪些生物学变化。发生在青春期乳房发育期间，导致晚年患癌症的风险更大。确定导致青春期乳腺发育异常的分子机制可能会导致制定了减少晚年乳腺癌负担的策略。当我们的身体使用我们消耗的糖作为能量时，它们会产生废弃的化学物质，称为其中一组代谢物被称为晚期糖基化终产物，简称 AGE。重要的是，除了糖分解产生的 AGE 之外，AGE 还通过食物的摄入和缺乏运动等外部环境因素会导致这种动态变化。平衡导致蛋白质功能障碍、蛋白质交联、遗传保真度降低、基因表达谱和异常细胞信号传导。我们的研究在动物模型中发现，高 AGE 饮食会显着改变乳房的发育方式。现在人们认识到肿瘤微环境在青春期发展中发挥着重要作用。促进乳腺发育和癌症进展，并且基质细胞信号传导的改变可以先于上皮细胞改变并作为致瘤过程的驱动因素，关键是高 AGE。饮食产生的乳房结构类似于具有过度增殖结构的肿瘤前病变我们还发现循环中的 AGE 水平显着升高。和乳腺癌患者的肿瘤组织，AGE 治疗改变癌症相关信号传导促进乳腺肿瘤生长的途径。本研究旨在明确高 AGE 饮食导致乳腺失调的机制青春期 (SA1) 和成年期 (SA2) 期间的腺体，并会询问观察到的变化是否会导致更高的风险乳腺肿瘤的形成和生长（SA3）。更深入地了解青春期 AGE 摄入量与乳房增大之间的联系癌症风险可能会为生活方式和药物干预定义新的潜在策略在确定的易感性窗口内降低乳腺癌风险。