Project 2 - Mechanisms linking Cancer Disparities and Metabolic Status

项目 2 - 连接癌症差异和代谢状态的机制

基本信息

批准号：
9977714
负责人：
Jodie Michelle Fleming
金额：
$ 30.14万
依托单位：
NORTH CAROLINA CENTRAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-20 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977714
关键词：
Address African American Automobile Driving Behavior Benzo(a)pyrene Binding Biochemical Bioenergetics Biological Biological Assay Biopsy Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer Risk Factor Breast Cancer cell line Carcinoma Cell Nucleus Cell physiology Cells ChIP-seq Clinical Clinical Data Communities Complex Computer Analysis DNA DNA Binding Data Data Analyses Diet Drug resistance Dyslipidemias Endocytosis Environment Environmental Risk Factor Ethnic Origin Ethnic group Fatty acid glycerol esters Future Gene Expression Generations Genetic Polymorphism Hepatic Hepatocyte High Fat Diet Homeostasis Hydrophobicity In Vitro Inflammation Inflammation Mediators Ingestion Insulin Intercellular Junctions Knowledge Lead Leptin Light Link Lipids Lipolysis Lipoprotein Receptor Lipoproteins Low income Luciferases Malignant Neoplasms Mammary Gland Parenchyma Measures Mediating Membrane Metabolic Molecular Neoplasm Metastasis Nuclear Obesity Outcome Pathology Pathway interactions Patient-Focused Outcomes Patients Phenotype Physiological Physiology Population Postmenopause Primary Neoplasm Proteins Proteomics ROCK1 gene Receptor Signaling Regulation Reporting Research Resistance Risk Factors Role Signal Transduction Testing The Cancer Genome Atlas Thinness Tight Junctions Tissues Toxic Environmental Substances Very low density lipoprotein Woman Xenograft Model bioaccumulation breast cancer progression cancer cell cancer health disparity cancer risk cancer stem cell cancer subtypes cell behavior diet and cancer extracellular health disparity in vitro Assay in vivo insight malignant breast neoplasm mammary epithelium migration mortality mouse model neoplastic cell new therapeutic target novel obesogenic outcome forecast overexpression pollutant promoter protein function receptor expression receptor function response social socioeconomics stem-like cell sugar toxicant transcriptome tumor tumor growth tumor initiation tumorigenesis uptake whole genome

项目摘要

Abstract This proposal addresses the relationship between African American (AA) and basal-like breast cancers, obesity, and environmental factors through a novel metabolically-regulated pathway that we have recently shown drives aggressive tumor cell behaviors. Combining in vitro studies with patient biopsy data and computational analyses, we will characterize the regulation and function of the widely expressed lipolysis stimulated lipoprotein receptor (LSR) in normal and transformed breast cells and tissue. LSR is a multifunctional protein known to mediate the endocytosis of lipoproteins and hydrophobic environmental toxicants such as benzo[α]pyrene in hepatocytes. Intriguingly, LSR is enriched at cell junctions and we are the first to show LSR is frequently translocated to the cell nucleus of non-surviving breast cancer (BrCa) patients. The function and underlying molecular mechanisms for these observations are unknown. Of note, studies show bodily accumulation of toxicants obtained through the diet promotes obesity and inflammation, and toxicant bioaccumulation higher in AAs and in low-income communities. Thus, we hypothesize that LSR expression and/or activity enhances aggressive BrCa phenotypes via modulation of cellular bioenergetics, toxicant bioaccumulation, and altered signal transduction and transcriptome regulation, thereby contributing to cancer disparities and poor patient outcome. In support, we recently demonstrated that LSR increases BrCa proliferation and migration, and enhances cancer stem cell-like and chemotherapeutic resistance features. Overexpression of LSR in a claudin-low BrCa cell line restores expression of genes involved in transformation, tumorigenesis, and tight junctions, thereby reverting these cells to other BrCa subtypes. Our pilot data show high LSR levels are significantly correlated with basal-like tumors, AA ethnicity, and diet-induced obesity. Our preliminary data also demonstrate that membrane-localized LSR mediates lipid endocytosis, thereby shifting cellular bioenergetics, while nuclear LSR binds DNA and was significantly associated with patient mortality in a pilot set of BrCa biopsies. To advance these preliminary studies we propose a dual approach, which includes delineating LSR's role in driving aggressive BrCa behaviors together with defining the molecular mechanisms of toxicant uptake and promotion inflammation in breast tissue. Specifically, we aims to (1) identify the LSR- driven pathways exploited during BrCa progression and the generation of aggressive cell behaviors, and (2) define the mechanisms of LSR-mediated lipid and toxicant uptake in BrCa cells, and the resultant effects on cancer bioenergetics and cell physiology. Our proposal may shed light on LSR as a biological link between obesity, inflammation, cancer disparities, and BrCa physiology. Novel knowledge obtained from the proposed studies will provide critical insight into the biological basis of dietary influences on breast cancer and may identify the LSR as a novel therapeutic target.

抽象的该建议涉及非裔美国人（AA）和类似基本的乳腺癌之间的关系，肥胖和环境因素通过我们最近有新型的代谢调节途径显示的驱动侵袭性肿瘤细胞行为。将体外研究与患者活检数据和计算分析，我们将表征广泛表达的脂解的调节和功能在正常和转化的乳腺细胞和组织中刺激的脂蛋白受体（LSR）。 LSR是一个多功能蛋白已知可介导脂蛋白和疏水环境的内吞作用肝细胞中的有毒物质，例如苯并[α] pyr。有趣的是，LSR在细胞连接处富含，我们是首先显示LSR经常被转移到非残疾乳腺癌（BRCA）患者的细胞核。这些观察结果的功能和基本分子机制尚不清楚。值得注意的是，研究显示通过饮食获得的毒物的身体积累可促进肥胖和感染，并在AA和低收入社区中，有毒的生物积累较高。那我们假设LSR 表达和/或活性通过调节细胞生物能学，增强了侵略性的BRCA表型，有毒的生物蓄积，并改变了信号转导和转录组调节，从而有助于癌症分布和患者效果不佳。为了支持，我们最近证明了LSR增加了BRCA 增殖和迁移，并增强癌症干细胞样和化学治疗性抗性特征。 LSR在claudin-low BRCA细胞系中的过表达恢复了与转化相关的基因的表达，肿瘤发生和紧密的连接处，从而将这些细胞恢复为其他BRCA亚型。我们的飞行员数据显示高LSR水平与碱性肿瘤，AA种族和饮食引起的肥胖症显着相关。我们的初步数据还表明，膜定位的LSR介导脂质内吞作用，从而转移细胞生物能学，而核LSR结合DNA，并且与患者死亡率显着相关 BRCA活检的飞行员。为了推进这些初步研究，我们提出了一种双重方法，其中包括描述LSR在推动侵略性BRCA行为中的作用，并定义分子机制乳房组织中的毒性摄取和促进注射。具体而言，我们的目的是（1）确定LSR- 在BRCA进展过程中探索的驱动途径和攻击性细胞行为的产生，（2）定义BRCA细胞中LSR介导的脂质和毒性摄取的机制，并对结果对癌症生物能和细胞生理学。我们的建议可能会阐明LSR作为生物学联系肥胖，感染，癌症分布和BRCA生理学。从提议中获得的新知识研究将为饮食对乳腺癌的影响的生物学基础提供重要的见解，可能将LSR识别为一种新型的治疗靶标。