ERR-gamma-dependent mammary tumorigenesis in response to BPA and a high-fat diet

BPA 和高脂饮食引起的 ERR-γ 依赖性乳腺肿瘤发生

• 批准号: 7895096
• 负责人: Rebecca B Riggins
• 金额: $ 7.68万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-16 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895096
• 关键词: Acetates; Affect; Affinity; Alleles; American; Animals; Anthracenes; Applications Grants; Automobile Driving; Binding; Breast Cancer Prevention; Carcinogens; Characteristics; Comorbidity; Complementary DNA; Data; Dependence; Development; Diabetes Mellitus; Diagnosis; Diet; Disease; Endocrine; Environment; Environmental Pollution; Environmental Risk Factor; Enzymes; Epidemic; Epithelial Cells; Exhibits; Exposure to; Family member; Fatty acid glycerol esters; Female; Fetus; Future; Gene Targeting; Genes; Genetic; Glycolysis; HK2 gene; Health; Hepatic; Hexokinase 2; Homeostasis; Human; Human Milk; Insulin; Insulin Resistance; Investigation; Knockout Mice; Link; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Measures; Mediating; Metabolism; Molecular; Molecular Target; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Orphan Receptor; Obesity; Outcome; PDH kinase; Pilot Projects; Play; Prediabetes syndrome; Predisposition; Production; Progesterone; Puberty; Publishing; Reducing diet; Risk; Risk Factors; Rodent; Role; Signal Transduction; Solid Neoplasm; Specificity; Sprague-Dawley Rats; Testing; Time; Tumor Tissue; Tumorigenicity; United States; Warburg Effect; Weaning; Woman; base; bisphenol A; cancer prevention; cancer risk; chemotherapy; diabetes risk; early life exposure; estrogen-related receptor; feeding; impaired glucose tolerance; in utero; in vivo; insulin sensitivity; malignant breast neoplasm; neonatal exposure; novel; overexpression; pyruvate dehydrogenase kinase 4; receptor; research study; response; tumor

DESCRIPTION (provided by applicant): Diet-induced obesity, insulin (INS) resistance, and type 2 diabetes have reached epidemic proportion among women in the United States, and each of these health problems significantly increase a woman's risk of developing breast cancer. Studies linking exposure to the endocrine disruptor Bisphenol A (BPA) with mammary tumorigenesis in rodents, poor survival outcome and response to chemotherapy in human breast cancer, and an increased risk for diabetes and INS resistance are suggestive of a shared signaling network responsive to this ubiquitous environmental contaminant. BPA readily crosses the placental barrier, appears to accumulate in the fetus, and is found in breast milk However, very little is known about the molecular mechanisms that regulate breast cancer development in response to co-morbidities like obesity and INS resistance, or how BPA functions in this context. While the true molecular target of BPA has been debated for some time, it is now known that this compound can bind with high affinity and specificity to the orphan nuclear receptor estrogen-related receptor gamma (ERR?). In our preliminary studies, we have found that a neonatal exposure to BPA impairs glucose tolerance in 2-month-old female Sprague Dawley rats, suggestive of early INS resistance, and hepatic expression of ERR? and two of its putative target genes (hexokinase 2, HK2; pyruvate dehydrogenase kinase 4, PDK4) are increased by BPA exposure in these animals. HK2 and PDK4 are essential enzymes of glycolysis, dysregulation of which is implicated in diabetes, INS resistance, and cancer. BPA also increases the expression of HK2 and PDK4 in MCF10A normal human mammary epithelial cells, and transient overexpression of ERR? cDNA mimics BPA's effect on HK2, suggesting that BPA-mediated changes in vivo are likely to be ERR?-dependent. Our central hypothesis is that early life exposure to BPA increases later mammary cancer risk by reducing INS sensitivity, and that this is mechanistically dependent upon ERR?, which we will test in two Specific Aims: Aim 1 will whether early life exposure to BPA and subsequent exposure to a high-fat diet reduces INS sensitivity and increases mammary tumorigenesis in wildtype mice, and whether this is reduced or fails to occur in mice exhibiting loss of one ERR? allele. Aim 2 will study ERR?, HK2, and PDK4 expression changes in the mammary glands and tumor tissues of ERR? mice and their wildtype counterparts to determine whether the activity of this glycolytic signaling network is associated with the INS resistance and tumorigenicity measures from Aim 1. Our proposed studies of INS resistance and mammary tumorigenesis in response to early life exposure to BPA and diet-induced obesity, and their dependence on the orphan nuclear receptor ERR?, represent a novel and mechanistic approach to the investigation of gene-environment-diet interactions, and are poised to make transformative contributions to our understanding of breast cancer prevention.

描述（由申请人提供）： 饮食引起的肥胖，胰岛素（INS）耐药性和2型糖尿病已经达到了美国女性的流行比例，这些健康问题中的每一个都大大增加了女性患乳腺癌的风险。将暴露与啮齿动物中的内分泌干扰物A（BPA）与乳腺肿瘤发生联系的研究，生存率差和对人类乳腺癌的化学疗法的反应以及糖尿病和INS耐药性的增加表明，对这种无散性环境的共享信号反应反应。 BPA很容易越过胎盘屏障，似乎在胎儿中积聚，但是在母乳中发现，对于响应肥胖和INS耐药性（例如肥胖症）或BPA在这种情况下如何起作用，这些分子机制几乎不知所措。虽然BPA的真正分子靶标已在一段时间内进行了争论，但现在知道该化合物可以与孤儿核受体雌激素相关受体伽马（ERR？）具有高亲和力和特异性结合。在我们的初步研究中，我们发现对BPA的新生儿暴露会损害2个月大的雌性Sprague Dawley大鼠的葡萄糖耐量，暗示着早期的INS耐药性和ERR的肝表达？这些动物的BPA暴露增加了其两个推定的靶基因（己二酶2，HK2；丙酮酸脱氢酶激酶4，PDK4）。 HK2和PDK4是糖酵解的必需酶，其失调与糖尿病，INS耐药性和癌症有关。 BPA还增加了MCF10A正常的人类乳腺上皮细胞中HK2和PDK4的表达，以及ERR的瞬时过表达？ cDNA模仿BPA对HK2的影响，表明BPA介导的体内变化可能是错误的？我们的核心假设是，早期生命暴露于BPA会通过降低INS敏感性来增加乳腺癌的风险，并且这在机械上取决于错误？我们将以两个具体的目的进行测试：目标1是否会在BPA上暴露于BPA，并随后暴露于高脂饮食会减少INS敏感性并降低乳腺象征性的效果，并在乳房中造成了症状的效果，并且是否会在Wild tumorigail tumorigail tumorigarigarigarigarigarigarigen thementy中脱颖而出。出现一个错误的小鼠？等位基因。 AIM 2会研究ERR？，HK2，并且PDK4表达在ERR的乳腺和肿瘤组织中会发生变化吗？小鼠及其野生型对应物，以确定该糖酵解信号网络的活性是否与目标1的INS耐药性和肿瘤性措施相关。我们提出的对ISS抗性和乳腺肿瘤发生的研究是针对早期寿命暴露于BPA和饮食诱导的肥胖症及其依赖性的方法，并指出了一种新颖的方法，并且是核心核能的依赖，并且是核心核能的依赖。基因环境 - 黎明的相互作用，并有望为我们对乳腺癌预防的理解做出变革性的贡献。