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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.

项目总结