Full Project 1: LSR Alters Metabolic Signaling to Drive Aggressive Breast Cancer Behaviors

完整项目 1：LSR 改变代谢信号以驱动侵袭性乳腺癌行为

• 批准号: 10247134
• 负责人: Keith Burridge
• 金额: $ 3.11万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-28 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247134
• 关键词: Address; Affect; African American; Aggressive behavior; Anabolism; Behavior; Binding; Bioenergetics; Biological; Biological Assay; Biological Factors; Breast; Breast Cancer Cell; Cancerous; Caucasians; Cell division; Cell physiology; Cells; Characteristics; Cholesterol; Chronic; Clinical; Collaborations; Cytoplasmic Tail; Data; Data Set; Diagnosis; Diet; Disease; Distant Metastasis; Endocytosis; Energy-Generating Resources; Environment; Etiology; Event; Fatty acid glycerol esters; Gene Chips; Gene Expression; Genes; Genetic Transcription; Glycogen; Goals; Guanosine Triphosphate Phosphohydrolases; Hepatic; High Fat Diet; Hospitals; In Vitro; Incidence; Lead; Leptin; Lesion; Link; Lipids; Lipolysis; Lipoprotein Receptor; Lipoproteins; Malignant - descriptor; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Measures; Mediating; Membrane; Membrane Lipids; Metabolic; Metabolic syndrome; Metabolism; Molecular; Mus; Neoplasm Metastasis; Nuclear; Obesity; Observational Study; Outcome; Pathway Analysis; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Phosphoproteins; Predisposition; Prevalence; Property; Proteins; Proteomics; Publishing; Race; Recurrence; Regulation; Research; Resistance; Resources; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Statistical Models; Testing; Tight Junctions; Tumor Subtype; Variant; Woman; Work; Xenograft procedure; anticancer research; cancer health disparity; cancer stem cell; cancer subtypes; cell behavior; effective therapy; epidemiology study; ethnic diversity; experimental study; glucose uptake; health disparity; improved; in vivo; insight; lipid metabolism; lipid transport; malignant breast neoplasm; metabolomics; mortality; new therapeutic target; novel; novel strategies; obesogenic; overexpression; racial disparity; receptor expression; receptor function; response; rho; rho GTP-Binding Proteins; stem; stem-like cell; therapeutic development; tumor; tumor behavior; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic; uptake

Project Summary/Abstract African American (AA) women have higher breast cancer mortality rates compared to other races. A greater prevalence of basal-like breast cancers in AA women explain some disparities, as these tumors are clinically the most aggressive, characterized by cancer stem No effective therapies exist and cell features. survival is poor. Escalating this disparity is the disease promoting effects of obesity, which is significantly higher in AA. The majority of studies on breast cancer disparities examine tumor characteristics, but the etiologic factors that lead to this disparity remain undefined. Our primary objective is to identify the mechanisms involved in promoting aggressive breast cancer in AAs, as a consequence of stromal effects at the site of the cancerous lesion. A key molecular pathway has been identified which integrates these clinical, microenvironmental and biological factors to affect tumor behavior. Aim 1 takes a novel approach, combining our published proteomic and gene expression datasets detailing race and tumor-subtype specific stromal interactions with our recently published data on the identified pathway promoting cancer stem cell- like, aggressive behaviors. Aims 2 and 3 extend these data to experimental studies to elucidate mechanistic details. To accomplish these tasks, our team established research partnerships that provides access to resources including the Normal Breast Study: a unique epidemiologic study from ethnically diverse patients at UNC Hospitals. There are several important biological implications of this work. The observation that AA breast tissue is enriched with distinct proteins, the prevalence of obesity in AA, and the predisposition to develop basal-like tumors strongly suggests a biological link between race, metabolism and cancer subtype. The role of differentially regulated metabolic-sensitive proteins in the tumor microenvironment will provide novel insights into the biological basis of racial disparities. The long-term goal of our collaboration is to understand tumor-microenvironment interactions and their influence on breast cancer disparities. Our distinctive approach will expose unique characteristics of the breast tissue microenvironment and will integrate advances in the field of tumor microenvironment with health disparities research. Relevance This proposal addresses breast cancer disparities by studying a key pathway that drive the aggressiveness of breast cancers. By combining observational studies on differences in this pathway by race, BMI, and breast cancer subtype with experimental studies to understand the role of this pathway in cellular phenotypes, this project will provide important and novel insight into the biological basis of racial disparities.

项目总结/摘要 非裔美国人（AA）女性的乳腺癌死亡率高于其他种族。更大 AA女性中基底细胞样乳腺癌的患病率解释了一些差异，因为这些肿瘤 临床上最具侵略性，其特征是癌症干没有有效的治疗方法存在， 细胞特征 生存很差。使这种差异升级的是肥胖症的疾病促进作用， 在AA中更高。大多数关于乳腺癌差异的研究检查肿瘤特征，但 导致这种差异的病因学因素仍然不明确。我们的主要目标是确定 作为基质效应的结果，AAs中参与促进侵袭性乳腺癌的机制， 癌性病变的部位。已经确定了一个关键的分子途径， 临床、微环境和生物学因素影响肿瘤行为。Aim 1采用了一种新颖的方法， 结合我们发表的蛋白质组学和基因表达数据集，详细说明了种族和肿瘤亚型特异性 基质相互作用与我们最近发表的关于促进癌症干细胞的已鉴定途径的数据， 比如攻击性行为目的2和3将这些数据扩展到实验研究，以阐明 续费为了完成这些任务，我们的团队建立了研究伙伴关系， 资源包括正常乳腺研究：一项来自不同种族患者的独特流行病学研究 在医院里。这项工作有几个重要的生物学意义。观察到AA 乳腺组织富含不同的蛋白质，AA中肥胖的患病率，以及 发生基底细胞样肿瘤强烈表明种族、代谢和癌症亚型之间存在生物学联系。 差异调节的代谢敏感蛋白在肿瘤微环境中的作用将提供 对种族差异的生物学基础的新见解。我们合作的长期目标是 了解肿瘤微环境的相互作用及其对乳腺癌差异的影响。我们 独特的方法将暴露乳房组织微环境的独特特征， 将肿瘤微环境领域的进展与健康差异研究相结合。 相关性 这项提案通过研究一个关键途径来解决乳腺癌的差异， 乳腺癌通过结合观察性研究，研究了不同种族、BMI和 乳腺癌亚型与实验研究，以了解这一途径的作用，在细胞 表型，这个项目将提供重要的和新的见解种族差异的生物学基础。