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：
10214618
负责人：
Jamie J Bernard
金额：
$ 37.87万
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214618
关键词：
4T1 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 Cultured Cells 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 Malignant Neoplasms Mammary Tumorigenesis Mass Spectrum Analysis Measures Mediating Metabolic Pathway Metabolism Modeling Mus Nature Obesity Outcomes Research Pathway interactions Phase Process Receptor Activation Receptor Signaling Research Risk Role Signal Transduction Testing Time Tissues Up-Regulation Visceral Work adduct carcinogenesis carcinogenicity cell transformation disorder risk feeding follow-up imaging approach in vivo inhibitor/antagonist malignant breast neoplasm mammary mammary epithelium multiphoton imaging neutralizing antibody novel overexpression receptor receptor expression receptor upregulation release factor 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.

项目概要这个 R01 是关于我们发现了一种令人惊讶和意想不到的方式，通过这种方式，脂肪组织可以增加乳腺上皮细胞对苯并（a）芘（BaP）（一种 I 类致癌物）的脆弱性，通过诱导芳烃受体（AhR）蛋白。 AhR 表达和转录的上调对于恶性转化的几个（如果不是全部）阶段。特别是，AhR 在人类乳腺癌中表达上调。 AhR 研究的一个主要差距是驱动乳腺中 AhR 诱导和激活的信号的性质致癌作用。到目前为止，没有人可能想到在寻找未知的激活剂和 AhR 的诱导剂，内脏脂肪组织 (VAT) 的分泌物就是其中之一。值得注意的是，我们的数据显示，VAT分泌的因子可以诱导乳腺上皮细胞中的AhR，并且AhR也被诱导在喂食高脂肪饮食的小鼠的乳腺组织中。我们的初步数据还强烈表明：1) BaP 和分泌物 VAT 中的成纤维细胞生长因子-2 (FGF2) 等协同作用导致 DNA 损伤并加速人乳腺上皮细胞的转化； 2) AhR 是 BaP 生物激活的关键控制点这个协同过程。我们的中心假设是人类 VAT 分泌的因子会增强 BaP 通过诱导 AhR 来促进新陈代谢，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众所周知的贡献者。我们将测试这个与人类乳腺癌有关的假设。在目标1中，我们将确定释放因素的影响来自 VAT 对 BaP 代谢和体外 DNA 损伤的影响。我们还将确定增值税中哪些内容会影响 BaP 代谢并诱导 AhR。在目标 2 中，我们将首次在体内确定高脂肪饮食的影响利用 AhR 介导的 BaP 代谢、DNA 损伤和乳腺肿瘤发生，利用急性和长期接触 BaP。为了实现这两个目标，我们将确定主要受体 FGFR1 信号传导的作用对于 FGF2，使用 FGFR1 抑制剂和新型原位模型研究 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 VAT 释放的因子相互作用促进 DNA 的机制和代谢途径损伤和乳腺癌。 BaP 代谢物将使用新型多光子成像方法进行分析。阐明人类内脏脂肪组织因素与生物活性苯并（a）芘（BaP）将是理解为什么肥胖会增加风险的重大进展乳腺癌。