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

项目总结/摘要 本研究的重点是早期生活因素及其对青春期乳房发育的影响， 它们与乳腺癌风险增加的关系。这时候我们还不了解什么生物变化 在青春期乳房发育期间发生，这导致在以后的生活中患癌症的风险更大。 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，它们会产生废物化学物质， 代谢物。其中一组代谢物被称为晚期糖基化终末产物或简称AGEs。 重要的是，除了由于糖的分解而产生外，AGE也通过糖的分解而形成。 食物摄入和外部环境因素，如缺乏锻炼。这种动态的变化 平衡导致蛋白质功能障碍、蛋白质交联、遗传保真度降低、基因改变 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发现，高AGEs的饮食显著改变了乳腺癌的发生， 在青春期发育。肿瘤微环境现在被认为在肿瘤发生中起着重要作用。 促进乳腺发育和癌症进展，以及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，高年龄 饮食在乳房中产生类似于具有过度增殖结构的肿瘤前病变的结构 以及基质细胞水平的增加。我们还表明，AGE水平显着升高，在循环 和乳腺癌患者的肿瘤组织，并且AGE治疗改变了癌症相关的信号传导 促进乳腺肿瘤生长的途径。 本研究旨在明确高AGE饮食引起乳腺癌细胞调节障碍的机制。 在青春期（SA 1）和成年期（SA 2）观察腺体，并询问观察到的变化是否会导致更高的风险， 乳腺肿瘤形成和生长（SA 3）。 对青春期AGE摄入量与乳房增大之间联系的更深入的机械理解 癌症风险可能定义新的潜在的生活方式和药物干预策略， 在确定的易感窗口期降低乳腺癌风险。

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.