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

基本信息

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
项目类别：
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

项目摘要

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）抵抗和2型糖尿病在美国女性中已达到流行比例，而这些健康问题中的每一个都显着增加了女性患乳腺癌的风险。将接触内分泌干扰物双酚 A (BPA) 与啮齿类动物乳腺肿瘤发生、人类乳腺癌生存结果不佳和化疗反应不佳以及糖尿病和 INS 耐药风险增加联系起来的研究表明，存在对这种普遍存在的信号反应的共享信号网络环境污染物。 BPA 很容易穿过胎盘屏障，似乎会在胎儿体内积聚，并在母乳中发现。然而，人们对调节乳腺癌发展以应对肥胖和 INS 抵抗等共病的分子机制，或者 BPA 如何调节乳腺癌的分子机制知之甚少。在此背景下发挥作用。虽然 BPA 的真正分子靶标已经争论了一段时间，但现在已知该化合物可以以高亲和力和特异性与孤儿核受体雌激素相关受体 γ (ERR?) 结合。在我们的初步研究中，我们发现新生儿接触 BPA 会损害 2 个月大的雌性 Sprague Dawley 大鼠的葡萄糖耐量，提示早期 INS 抵抗以及 ERR？其两个假定的靶基因（己糖激酶 2，HK2；丙酮酸脱氢酶激酶 4，PDK4）会因这些动物中 BPA 暴露而增加。 HK2 和 PDK4 是糖酵解的必需酶，其失调与糖尿病、INS 抵抗和癌症有关。 BPA 还增加 MCF10A 正常人乳腺上皮细胞中 HK2 和 PDK4 的表达，以及 ERR？ cDNA 模拟了 BPA 对 HK2 的影响，表明 BPA 介导的体内变化可能是 ERR?依赖性的。我们的中心假设是，生命早期接触 BPA 会降低 INS 敏感性，从而增加日后患乳腺癌的风险，并且这在机制上取决于 ERR？，我们将在两个具体目标中进行测试：目标 1 是否会影响生命早期接触 BPA 以及随后的乳腺癌风险。暴露于高脂肪饮食会降低野生型小鼠的 INS 敏感性并增加乳腺肿瘤的发生，而在表现出 1 个 ERR 缺失的小鼠中，这种情况是否会减少或不会发生？等位基因。目标2将研究ERR？、HK2和PDK4在ERR？的乳腺和肿瘤组织中的表达变化。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 中的 INS 抗性和致瘤性措施相关。我们提出的 INS 抗性和乳腺肿瘤发生研究，以响应早期接触 BPA 和饮食诱导的肥胖以及它们对孤儿核受体 ERR? 的依赖，代表了一种研究基因-环境-饮食相互作用的新颖的机械方法，并准备为我们对乳腺癌的理解做出变革性的贡献预防。