Mechanistic role of obesity in benzo(a)pyrene-initiated cancer

肥胖在苯并（a）芘引发的癌症中的机制作用

基本信息

批准号：
10621721
负责人：
Jamie J Bernard
金额：
$ 37.54万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-13 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621721
关键词：
4T1 Acceleration Acute Adipose tissue Agar Aromatic Polycyclic Hydrocarbons Aryl Hydrocarbon Receptor Benzo(a)pyrene Breast Cancer Risk Factor Breast Carcinogenesis Breast Epithelial Cells Cancer Burden Carcinogens Cells Central obesity Chronic Classification DNA Damage Data EPHX1 gene Enzymes Epoxy Compounds Etiology Exposure to FGF2 gene FGFR1 gene Fibroblast Growth Factor Receptor 2 Fibroblasts Gene Expression Genetic Transcription Growth Growth Factor High Fat Diet Human Hydrolase In Vitro Inbred BALB C Mice Individual Lead MCF10A cells Malignant - descriptor Mammary Tumorigenesis Mass Spectrum Analysis Measures Mediating Metabolic Pathway Metabolism Modeling Mus Nature Obesity Outcomes Research Pathway interactions Phase Process Pyrenes Receptor Activation Receptor Signaling Receptor Up-Regulation Research Risk Role Signal Transduction Testing Time Tissues Up-Regulation Visceral Work adduct antagonist cancer initiation carcinogenesis carcinogenicity cell transformation disorder risk feeding follow-up imaging approach in vivo inhibitor malignant breast neoplasm mammary mammary epithelium multiphoton imaging neutralizing antibody novel overexpression receptor receptor expression receptor upregulation release factor synergism transcriptome sequencing tumor tumorigenesis

项目摘要

Project Summary This R01 is about our discovery of a surprising and unexpected way in which adipose tissue increases the vulnerability of mammary epithelial cells to benzo(a)pyrene (BaP), a Group I-classified carcinogen, by inducing the aryl hydrocarbon receptor (AhR) protein. Upregulation of AhR expression and transcription is important in several, if not all, stages of malignant transformation. In particular, AhR is upregulated in human breast cancer. A major gap in AhR research is the nature of the signals that drive AhR induction and activation in breast carcinogenesis. Until now, no one might have expected that in the search for the unknown activators and inducers of AhR, that secretions from visceral adipose tissue (VAT) would be among them. Remarkably, our data shows that factors secreted from VAT can induce AhR in mammary epithelial cells, and AhR is also induced in mammary tissues of mice fed a high-fat diet. Our preliminary data also strongly suggest: 1) BaP and secretions from VAT, such as fibroblast growth factor-2 (FGF2), synergize to cause DNA damage and accelerated transformation of human mammary epithelial cells; and 2) AhR is a critical control point for BaP bioactivation in this synergistic process. Our central hypothesis is that factors secreted from human VAT will potentiate BaP metabolism by inducing AhR, resulting in increased carcinogenic metabolites (e.g. BPDE) and DNA damage, two well-known contributors to malignant transformation of human mammary epithelial cells. We will test this hypothesis in connection with human breast cancer. In aim 1, we will determine the impact of factors released from VAT on BaP metabolism and DNA damage in vitro. We will also determine what is in VAT that effects BaP metabolism and induces AhR. In aim 2, we will determine for the first time in vivo the impact of high-fat diet feeding on AhR-mediated BaP metabolism, DNA damage and mammary tumorigenesis using both acute and chronic exposures to BaP. For both aims, we will determine the role of FGFR1 signaling, the primary receptor for FGF2, on the AhR activation and metabolism of BaP using a FGFR1 inhibitor and a novel orthotopic model of FGFR1-driven mammary tumorigenesis. The expected outcomes of this research will be to identify the mechanisms and metabolic pathways by which BaP interacts with factors released from VAT in promoting DNA damage and breast cancer. BaP metabolites will be analyzed using a novel multiphoton imaging approach. Elucidating the unexpected and surprising connection between factors from human visceral adipose tissues and the bioactivation benzo(a)pyrene (BaP) will be a major advance in understanding why obesity heightens the risk of breast cancer.

项目摘要该R01是关于我们发现了一种令人惊讶且出乎意料的方式，脂肪组织会增加通过诱导乳腺上皮细胞对苯并（A）pyrene（BAP）的脆弱性，I组通过诱导芳基烃受体（AHR）蛋白。 AHR表达和转录的上调在几个（如果不是全部）恶性转化的阶段。特别是，AHR在人类乳腺癌中被上调。 AHR研究的一个主要差距是信号的性质，这些信号驱动AHR诱导和乳房激活致癌作用。到目前为止，没有人可能期望在寻找未知激活剂和 AHR的诱导者，其中包括内脏脂肪组织（VAT）的分泌物。值得注意的是，我们的数据表明，从增值税分泌的因素可以诱导乳腺上皮细胞中的AHR，并且还诱导了AHR 在喂养高脂饮食的小鼠的乳腺组织中。我们的初步数据也强烈建议：1）BAP和分泌物从增值税（例如成纤维细胞生长因子2（FGF2））协同作用以引起DNA损伤并加速人类乳腺上皮细胞的转化； 2）AHR是BAP生物活化的关键控制点这个协同过程。我们的中心假设是，人类增值税分泌的因素将增强BAP 通过诱导AHR代谢，导致致癌代谢物（例如BPDE）和DNA损伤增加人类乳腺上皮细胞恶性转化的两个知名贡献者。我们将测试这个与人类乳腺癌有关的假设。在AIM 1中，我们将确定释放因素的影响从BAP代谢和DNA损伤的体外增值税。我们还将确定效果bap的增值税中的什么代谢并诱导AHR。在AIM 2中，我们将在体内首次确定高脂饮食的影响以AHR介导的BAP代谢，DNA损伤和使用急性和长期暴露于BAP。对于这两个目标，我们将确定FGFR1信号的作用，主要受体对于FGF2，使用FGFR1抑制剂和新型的原位模型对BAP的AHR激活和代谢 FGFR1驱动的乳腺肿瘤发生。这项研究的预期结果将是确定 BAP与从增值税释放的因素相互作用的机理和代谢途径促进DNA 损害和乳腺癌。 BAP代谢物将使用新型的多光子成像方法进行分析。阐明人类内脏脂肪组织中因素之间的意外和令人惊讶的联系生物活化苯并（a）pyrene（BAP）将是理解为什么肥胖升高风险的重大进步乳腺癌。