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

• 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
• 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

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 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，脂肪组织通过这种方式增加了 诱导乳腺上皮细胞对苯并(A)芘(BaP)的易感性 芳香烃受体(AhR)蛋白。AhR的表达和转录上调在肺癌中具有重要意义 恶变的几个阶段，如果不是全部的话。特别是，AhR在人类乳腺癌中上调。 AhR研究中的一个主要空白是驱动乳腺AhR诱导和激活的信号的性质 致癌。到目前为止，可能没有人预料到，在寻找未知的激活剂和 来自内脏脂肪组织(VAT)的分泌物将是AhR的诱导者。值得注意的是，我们的 数据表明，VAT分泌的因子可诱导乳腺上皮细胞AhR，也可诱导AhR 在喂食高脂饮食的小鼠的乳房组织中。我们的初步数据也有力地表明：1)BaP和分泌物 从VAT中，如成纤维细胞生长因子-2(FGF2)，协同作用引起DNA损伤并加速 2)AhR是BaP生物激活的关键控制点。 这种协同作用的过程。我们的中心假设是，人类增值税分泌的因素会增强BaP 通过诱导AhR代谢，导致致癌代谢物(如BPDE)增加和DNA损伤； 人类乳腺上皮细胞恶变的两个已知贡献者。我们将对此进行测试 与人类乳腺癌有关的假说。在目标1中，我们将确定释放的因素的影响 VAT对体外BaP代谢和DNA损伤的影响。我们还将确定增值税中哪些内容会影响BaP 新陈代谢，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 以AhR介导的BaP代谢、DNA损伤和乳腺肿瘤发生为食 长期接触苯并苯。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抑制剂和一种新的原位模型研究BaP的AhR激活和代谢 关于FGFR1驱动的乳腺肿瘤发生的研究。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。将使用一种新的多光子成像方法来分析BaP代谢物。 阐明人类内脏脂肪组织中的因子与 生物活化苯并(A)芘(Bap)将是理解肥胖增加风险的重大进展。 乳腺癌的风险。