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

• 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
• 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

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 这项研究的重点是早期生命因素及其对青春期和青春期乳腺发展的影响 它们与增加的乳腺癌风险有关。目前，我们不了解什么生物学变化 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。 确定引起异常乳腺乳腺发育的分子机制可能导致 定义的策略可以减少后来的乳腺癌燃烧。 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。这样的一组代谢产物被称为高级糖基化终产物或年龄。 由于糖分的破裂，与他们的生产不同，年龄也是通过 摄取食物和外部环境因素，例如缺乏运动。这种动态的变化 平衡会导致蛋白质功能障碍，蛋白质交联，改善遗传保真度，改变基因 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段高的饮食会显着改变乳房 青春期的发展。肿瘤微环境现在已被公认为在 促进乳腺发育和癌症进展，并改变基质细胞信号的改变 可以先于上皮细胞改变并充当肿瘤过程的驱动因素。批判性的年龄很高 饮食在乳房中产生类似于肿瘤前病变的乳房结构 并增加基质细胞水平。我们还表明，流通中的年龄水平显着升高 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物干预的新型潜在策略 在明确的敏感性窗口中降低乳腺癌的风险。