Identifying mechanisms linking stress biology to human breast cancer

描述(由申请人提供)：在社会环境的背景下理解人类癌症对于优化癌症预防和护理至关重要。通过确定影响患者神经内分泌生理和随后的肿瘤生物学的应激机制，我们将增加对肿瘤生物学的理解。神经内分泌系统将行为和经验与激素分泌(如雌激素和皮质醇)联系起来，导致激素诱导的肿瘤细胞及其微环境中基因表达的变化。然而，慢性应激在乳腺肿瘤生物学中的作用的细胞和分子机制仍然知之甚少。由于在人类群体中发现了复杂的遗传和环境变化，确定应激反应影响癌症生物学的细胞和分子机制将需要跨学科的方法来研究已经用于研究癌症的传统模型。康森和麦克林托克的实验室已经开发出这样一种方法来研究社会压力在两种互补的人类乳腺癌啮齿动物模型中的作用。我们发现，长期的社会隔离会导致糖皮质激素对叠加应激源的反应增强；反过来，乳腺基因的表达和形态表明，在腺体发育过程中脂肪组织结构发生了变化。此外，社会隔离和随之而来的压力(糖皮质激素介导的)反应性的增加与乳腺脂肪代谢的显著增加有关，甚至在浸润性癌症发展之前就是如此。基于这些数据，我们建议通过确定乳腺脂肪组织及其旁分泌对肿瘤生长的影响来研究基因表达的变化，以及有助于肿瘤生长速度增加的分泌蛋白和因素。我们预测，这些研究的完成将揭示新的应激诱导的微环境影响乳腺肿瘤生长的机制。 公共卫生相关性：乳腺癌健康差异表明，尽管乳腺癌的总体发病率较低，但非裔美国女性的预后较差，这不能仅归因于治疗差异。使用两个乳腺癌动物模型，使我们能够严格控制社会环境，这个双重PI项目将检验长期社会孤立和随之而来的压力反应对乳腺癌生物学结果产生负面影响的假设。预计在这些模型中所作的观察将建议针对非洲裔美国人和其他妇女的这些生物过程采取具体的预防性干预措施，这些妇女由于影响健康差距的社会环境而处于社会孤立的高度风险。

DESCRIPTION (provided by applicant): Understanding human cancer in the context of the social environment is essential for optimizing cancer prevention and care. By identifying stress mechanisms that impact on a patient's neuroendocrine physiology and subsequent tumor biology, we will increase our understanding of tumor biology. The neuroendocrine system links behavior and experience with hormone secretion (e.g. estrogen and cortisol) resulting in hormone-induced gene expression changes within both tumor cells and their microenvironment. However, the cellular and molecular mechanisms underlying the role of chronic stress in breast tumor biology remain poorly understood. Because of the complex genetic and environmental variation found in human populations, identifying the cellular and molecular mechanisms through which stress responses affect cancer biology will require transdisciplinary approaches to traditional models already used for studying cancer. The Conzen and McClintock laboratories have developed such an approach to studying the role of social stress in two complementary rodent models of human breast cancer. We discovered that chronic social isolation leads to a heightened glucocorticoid response to a superimposed stressor; in turn, mammary gland gene expression and morphology suggest an alteration in adipose tissue architecture during gland development. Moreover, social isolation and the ensuing increased stress (glucocorticoid-mediated) reactivity are associated with a significant increase in mammary gland fat metabolism, even prior to invasive cancer development. Based on these data, we propose to study mammary gland fat tissue and its paracrine effects on tumor growth by identifying the gene expression changes as well as the secreted proteins and factors that can contribute to increased tumor growth rates. We predict that completion of these studies will uncover novel stress-induced microenvironment mechanisms affecting mammary tumor growth. PUBLIC HEALTH RELEVANCE: Breast cancer health disparities suggest that despite a lower overall incidence of breast cancer, African- American women have a poorer outcome that cannot be ascribed to treatment disparities alone. Using two animal models of breast cancer that allow us to tightly control the social environment, this dual PI project will examine the hypothesis that chronic social isolation and the ensuing stress response negatively influences the biological outcome of breast cancer. Observations made in these models are expected to suggest specific preventive interventions aimed at these biological processes for African-American and other women who are at high risk of social isolation due to societal circumstances that impact on health disparities.