Identifying mechanisms linking stress biology to human breast cancer

描述（由申请人提供）：在社会环境背景下了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学和随后的肿瘤生物学的应激机制，我们将增加我们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，从而导致肿瘤细胞及其微环境中激素诱导的基因表达变化。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。由于在人群中发现了复杂的遗传和环境变异，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。Conzen和McClintock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压力源的反应增强；反过来，乳腺基因表达和形态学表明在腺体发育过程中脂肪组织结构发生了改变。此外，社会隔离和随之而来的应激（糖皮质激素介导）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。在此基础上，我们拟进一步研究乳腺脂肪组织及其旁分泌对肿瘤生长的影响，确定其基因表达变化，以及促进肿瘤生长的分泌蛋白和因子。我们预测这些研究的完成将揭示影响乳腺肿瘤生长的新的应激诱导微环境机制。

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.