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Determine the molecular and metabolic mechanisms by which A-FABP links dysregulated lipid metabolism-induced obesity/breast cancer risk

确定 A-FABP 与脂质代谢失调引起的肥胖/乳腺癌风险相关的分子和代谢机制

基本信息

批准号：
10501614
负责人：
Bing Li
金额：
$ 117.85万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-12 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10501614
关键词：
Address Adipocytes Adipose tissue Affect Basic Science Breast Breast Cancer Cell Breast Cancer Patient Breast Cancer Risk Factor Cellular Metabolic Process Chronic Clinical Comprehensive Cancer Center Consumption Data Development FABP4 gene Fatty acid glycerol esters Fish Oils Funding Opportunities Health High Fat Diet Human Immune Immunosuppression Immunotherapy Inflammation Insulin Interleukin-6 Iowa Knockout Mice Leptin Link Linoleic Acids Lipids Mammary Neoplasms Measures Mediating Metabolic Molecular Molecular Chaperones Monoclonal Antibodies Mus Obesity Oleic Acids Olive oil preparation Omega-3 Fatty Acids PDL1 pathway Palmitic Acids Pathway interactions Peripheral Phenotype Physician Executives Postmenopause Prevention Prevention strategy Regulation Research Risk Role Sampling Serum Shapes Source Specimen Therapeutic antibodies Thinness Tissues Treatment Efficacy Tumor-Derived Tumor-associated macrophages Universities Unsaturated Fats Woman Xenograft Model adiponectin base cancer clinical trial cancer immunotherapy cancer risk cocoa butter conditional knockout design diet-induced obesity epidemiology study extracellular fatty acid-binding proteins humanized antibody improved insight lipid metabolism macrophage malignant breast neoplasm metabolic profile monocyte mortality mouse model new therapeutic target novel novel strategies novel therapeutic intervention obesity biomarkers oxidation programs response saturated fat targeted biomarker tumor tumor growth tumorigenic

项目摘要

The objective of this proposal is to determine how high fat diet (HFD)-induced lipid dysregulation links obesity with increased breast cancer (BC) risk. Epidemiologic studies have confirmed that obesity increases the risk and mortality of BC, but the molecular mechanisms of obesity/breast cancer associations remain largely unknown. Our recent studies demonstrate that lipid chaperone A-FABP (adipose fatty acid binding protein, also known as FABP4) promotes obesity-associated BC by intracellular regulating pro-tumor activity in tumor associated macrophages (TAMs) and extracellular enhancing aggressive phenotype of BC cells. Thus, A- FABP might represent a new factor linking dysregulated lipid metabolism with obesity/BC risk. Moreover, we observed that obesity can be induced by consumption of different types of HFDs, including saturated fats (e.g. cocoa butter) or unsaturated fats (e.g. olive oil, fish oil). However, only cocoa butter HFD-induced obesity was associated with increased A-FABP expression and mammary tumor growth. These observations suggest a novel concept that not all HFD-induced obesity is tumorigenic. Given the undefined links underlying obesity- induced BC risk, we hypothesized that HFDs rich in saturated fats promote BC risk through A-FABP-mediated immune and metabolic regulations. As such, A-FABP offers a novel therapeutic target and biomarker for obesity-associated BC risk. Three complementary but independent specific aims are designed to address our central hypothesis. Aim 1 is to determine the molecular mechanisms by which different HFDs upregulate A- FABP for BC risk. We will identify which HFDs promote mammary tumor risk and further dissect how the “bad” fat drives intracellular A-FABP expression in TAMs and promotes extracellular A-FABP secretion from adipocytes. Aim 2 is to delineate the downstream metabolic mechanisms of HFD-upregulated A-FABP in BC risk and immunotherapy. We will delineate how intracellular A-FABP in TAMs regulates the FA oxidation (FAO)/HIF2α/PD-L1 pathway for immune suppressive function, followed by delineation of how extracellular A- FABP reprograms lipid metabolic profile in BC cells to enhance their aggressive phenotype. We will further evaluate if blocking A-FABP activity with our unique humanized antibodies improves A-FABP-induced metabolic dysregulation and reduces obesity/BC risk. Aim 3 is to evaluate A-FABP as a biomarker for obesity- associated BC in humans. We will determine the function of A-FABP in peripheral monocytes and measure the levels of soluble A-FABP in serum and A-FABP expression in tumor stroma using specimens collected from lean and obese women with or without BC. Successful completion of this proposal will determine the “bad HFDs” in promoting BC risk and identify the molecular and metabolic mechanisms by which A-FABP mediates the pro-tumorigenic activities in HFD-induced obesity/BC risk.

本提案的目的是确定高脂肪饮食（HFD）诱导的脂质失调与肥胖之间的关系