Identifying mechanisms linking stress biology to human breast cancer

确定应激生物学与人类乳腺癌之间的联系机制

基本信息

批准号：
8669922
负责人：
Suzanne Daniela Conzen
金额：
$ 30.97万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-20 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8669922
关键词：
ATP Citrate (pro-S)-Lyase Acute Adipocytes Adipose tissue Adult Affect African American Age Animal Model Animals Antigens Architecture Behavior Behavioral Biochemical Biological Biological Process Biology Breast Breast Cancer Model Breast Diseases Breast Epithelial Cells Cancer Biology Cell Survival Chronic Chronic stress Complex Conflict (Psychology)Data Development Duct (organ) structure Ductal Epithelial Epithelial Cell Proliferation Estradiol Estrogen Receptor Status Estrogen Receptors Estrogens Exhibits Exposure to FVB/N Mouse Fatty acid glycerol esters Figs - dietary Fright Gene Expression Gene Expression Profile Genes Genetic Glucocorticoid Receptor Glucocorticoids Goals Growth Hexokinase 2 Hormones Housing Human Hydrocortisone Incidence Inflammation Laboratories Link Lipid Synthesis Pathway Lipids Lipolysis Lymphocyte Malignant - descriptor Malignant Neoplasms Mammals Mammary Neoplasms Mammary gland Measures Mediating Metabolic Modeling Molecular Morphology Mouse Strains Mus Neurosecretory Systems Outcome Pathway interactions Patients Physiological Physiology Population Premalignant Preventive Intervention Process Proteins RNA Rattus Recurrence Research Rodent Rodent Model Role Signal Transduction Simian virus 40 Social Environment Social isolation Sprague-Dawley Rats Stress Structure Testing Tissues Transgenic Mice Trees Tumor Biology Up-Regulation Variant Weaning Woman base biological adaptation to stress cancer care cancer health disparity cancer prevention cell growth experience gland development health disparity high risk lipid metabolism macrophage malignant breast neoplasm mammary epithelium middle age mouse model neoplastic cell novel paracrine research study response social stress stressor tumor tumor growth vigilance

项目摘要

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.

描述（由申请人提供）：了解社会环境背景下的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，我们将增进对肿瘤生物学的理解。神经内分泌系统将行为和体验与激素分泌（例如雌激素和皮质醇）联系起来，导致肿瘤细胞及其微环境内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背后的细胞和分子机制仍然知之甚少。由于人类中存在复杂的遗传和环境变异，识别应激反应影响癌症生物学的细胞和分子机制将需要对已经用于研究癌症的传统模型采取跨学科的方法。 Conzen 和 McClintock 实验室开发了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，长期的社会孤立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表明腺体发育过程中脂肪组织结构发生变化。此外，社会隔离和随之而来的压力（糖皮质激素介导的）反应性增加与乳腺脂肪代谢的显着增加有关，甚至在侵袭性癌症发生之前也是如此。基于这些数据，我们建议通过识别基因表达变化以及可能导致肿瘤生长速率增加的分泌蛋白和因子来研究乳腺脂肪组织及其对肿瘤生长的旁分泌作用。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。