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

• 批准号: 9750532
• 负责人: Jodie Michelle Fleming
• 金额: $ 29.86万
• 依托单位: NORTH CAROLINA CENTRAL UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9750532
• 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; 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

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 该提案解决了非裔美国人 (AA) 与基底样乳腺癌之间的关系， 肥胖和环境因素通过我们最近发现的一种新的代谢调节途径 显示驱动肿瘤细胞的侵袭性行为。将体外研究与患者活检数据相结合 通过计算分析，我们将描述广泛表达的脂肪分解的调节和功能 刺激正常和转化乳腺细胞和组织中的脂蛋白受体（LSR）。液态硅橡胶是一种 已知介导脂蛋白内吞作用和疏水环境的多功能蛋白质 肝细胞中的苯并[α]芘等有毒物质。有趣的是，LSR 在细胞连接处富集，而我们是 首先表明 LSR 经常易位至非存活乳腺癌 (BrCa) 患者的细胞核。 这些观察结果的功能和潜在分子机制尚不清楚。值得注意的是，研究 显示通过饮食获得的有毒物质在体内积累会促进肥胖和炎症，并且 AA 地区和低收入社区的有毒物质生物累积率较高。因此，我们假设 LSR 表达和/或活性通过调节细胞生物能增强侵袭性 BrCa 表型， 有毒物质的生物积累，并改变信号转导和转录组调节，从而有助于 癌症差异和患者预后不佳。作为支持，我们最近证明 LSR 可以增加 BrCa 增殖和迁移，并增强癌症干细胞样和化疗耐药性特征。 在密蛋白低 BrCa 细胞系中过表达 LSR 可恢复参与转化的基因表达， 肿瘤发生和紧密连接，从而将这些细胞恢复为其他 BrCa 亚型。我们的试点数据显示 高LSR水平与基底样肿瘤、AA种族和饮食引起的肥胖显着相关。我们的 初步数据还表明，膜定位的 LSR 介导脂质内吞作用，从而改变 细胞生物能学，而核 LSR 结合 DNA，与患者死亡率显着相关 BrCa 活检试验集。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 在驱动攻击性 BrCa 行为中的作用并定义分子机制 毒物吸收并促进乳腺组织炎症。具体来说，我们的目标是 (1) 识别 LSR- BrCa 进展和侵袭性细胞行为产生过程中利用的驱动途径，以及 (2) 定义了 BrCa 细胞中 LSR 介导的脂质和毒物摄取的机制，以及由此产生的影响 癌症生物能量学和细胞生理学。我们的建议可能会阐明 LSR 作为两者之间的生物联系 肥胖、炎症、癌症差异和 BrCa 生理学。从提议中获得的新知识 研究将为饮食对乳腺癌影响的生物学基础提供重要的见解，并可能 将LSR确定为新的治疗靶点。