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：
10625616
负责人：
Victoria Jane Findlay
金额：
$ 40.97万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-21 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625616
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.

项目摘要/摘要这一点的重点是早期生活因素及其对青春期期间乳腺发展的影响它们与乳腺癌的风险增加有关。发生在青春期乳腺发育期间，这会导致晚年患癌症的风险更大。确定引起阿贝兰特青春期乳腺发育的分子机制可能导致定义的策略可以减轻后来的乳腺癌负担。当我们的身体使用我们消耗的糖以产生的糖，它们会产生被称为的废物化学物质代谢物。由于糖分的崩溃而批判性地从生产中产生，年龄都是通过你形成的摄入食物和外部环境因素，例如缺乏运动。平衡会导致蛋白质功能障碍，蛋白质交联，遗传保真度降低，改变了Genee 表达谱和异常细胞信号传导。我们的研究已经在动物模型中确定了年龄较高的饮食习惯，从而显着改变了乳房在青春期中发展。促进乳腺发育和癌症进展，并改变基质细胞信号的改变可以在上皮细胞植物和肿瘤过程的驱动器之前。饮食在乳房中产生类似于肿瘤前病变的乳房结构并增加了基质细胞的水平。乳腺癌患者的肿瘤组织以及年龄治疗改变了癌症相关的信号促进乳腺肿瘤生长的途径。这项研究旨在定义高年级饮食引起乳腺失调的机制青春期（SA1）和成年期（SA2）期间的腺体会询问观察到的变化是否导致更高的风险乳腺肿瘤形成和生长（SA3）。对青春期和乳房增加的年龄摄入量之间的联系有更大的机械理解癌症风险可能定义了针对生活方式和药理学干预的新型潜在策略在定义的敏感性窗口中降低乳腺癌风险。