HGF signaling in African-American and Basal-like Breast Cancer

非裔美国人乳腺癌和基底样乳腺癌中的 HGF 信号传导

• 批准号: 8726349
• 负责人: Jodie Michelle Fleming
• 金额: $ 15.1万
• 依托单位: NORTH CAROLINA CENTRAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8726349
• 关键词: Acinus organ component; Address; African; African American; Antibodies; Behavior; Biological; Biological Assay; Biological Models; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Carcinoma; Cancerous; Caucasians; Caucasoid Race; Cell Line; Cells; Characteristics; Coculture Techniques; Collaborations; Data; Development; Epidemiologic Studies; Exposure to; Fibroblasts; Gene Expression; Gene Expression Profile; Genes; Goals; High Prevalence; Hospitals; Immunohistochemistry; In Vitro; Incidence; Lead; Learning; Lesion; Link; Liver Fibrosis; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Measures; Methods; Microarray Analysis; Modeling; Molecular; Molecular Profiling; Molecular Target; Normal tissue morphology; Observational Study; Pathway interactions; Patients; Phenotype; Play; Premenopause; Prevention; Proteins; Proteomics; Race; Regulation; Research; Resources; Risk; Role; Signal Pathway; Signal Transduction; Site; Solid Neoplasm; Specimen; Statistical Models; Testing; Tissues; Tumor Biology; Up-Regulation; Variant; Western Blotting; Woman; Work; base; cancer cell; cancer health disparity; caucasian American; cell behavior; cell motility; cytokine; hormone metabolism; inhibitor/antagonist; insight; malignant breast neoplasm; migration; mortality; neoplastic cell; novel; overexpression; paracrine; programs; protein expression; public health relevance; research study; small hairpin RNA; social; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): Premenopausal African-American women suffer disproportionately from a higher incidence of the basal-like "triple-negative" breast cancer compared to Caucasian-American patients. Currently, no effective molecular therapies exist for this highly aggressive cancer and, consequently, patient survival is poor. The majority of studies investigating differences in breast cancer between African- and Caucasian-American women examine tumor characteristics, however, the etiologic factors that lead to this disparity remain undefined. Our preliminary data implicate a role for HGF in breast cancer progression and in differences between African-American and Caucasian patients. To further understand the role of this pathway in cancer disparities we will address two Aims. Aim 1 will identify a gene expression signature for HGF via microarray analysis and use this signature to evaluate the expression of the HGF pathway in African-American vs. Caucasian patients and according to breast cancer subtype. Aim 2 will use primary cell lines from African- American and Caucasian patients to evaluate the effects of variation in HGF expression by fibroblasts on cancer cell phenotypes including proliferation and motility assays. Thus, our primary objective is to identify the mechanisms involved in the development of aggressive, metastatic breast cancer in premenopausal African-Americans, as a consequence of stromal effects at the site of the cancerous lesion. Our team has established research partnerships that provide access to resources including the Normal Breast Study: a unique epidemiologic study of normal tissue from ethnically diverse patients at UNC Hospitals. There are several important biological implications of this work. Tumor biology often takes advantage of existing normal tissue programs. By studying the cancer-adjacent tissue, in combination with tissue adjacent to tumor, we will learn which normal programs the tumor utilizes for progression, and these pathways may be targetable. The observation that the normal breast tissue of African-American women is enriched with proteins from programs distinct from Caucasian women, and that African-American women are predisposed to develop basal-like breast cancer strongly suggests a biological link between race and cancer subtype. The role of differentially regulated stromal-derived proteins in the tumor microenvironment will provide novel insights into the biological basis of racial disparities. The long-term goal of the Fleming-Troester collaboration is to understand tumor-microenvironment interactions and their influence on breast cancer disparities.

描述（由申请人提供）：绝经前非裔美国妇女与美国白人患者相比，基底样“三阴性”乳腺癌的发病率不成比例地高。目前，对于这种高度侵袭性的癌症，还没有有效的分子疗法，因此，患者的存活率很低。大多数调查非洲裔和高加索裔美国女性乳腺癌差异的研究检查了肿瘤特征，然而，导致这种差异的病因仍未明确。我们的初步数据暗示了HGF在乳腺癌进展中的作用以及非裔美国人和白种人患者之间的差异。为了进一步了解这一途径在癌症差异中的作用，我们将解决两个目标。目的1将通过微阵列分析确定HGF的基因表达特征，并根据乳腺癌亚型，使用该特征来评估非裔美国人与白人患者中HGF通路的表达。目的2将使用来自非裔美国人和白种人患者的原代细胞系来评估成纤维细胞HGF表达变化对癌细胞表型的影响，包括增殖和运动测定。因此，我们的主要目的是确定绝经前非洲裔美国人的侵袭性转移性乳腺癌的发展机制，这是癌变部位间质作用的结果。我们的团队已经建立了研究伙伴关系，提供了包括正常乳房研究在内的资源：一项独特的流行病学研究，来自北卡罗来纳大学医院不同种族的患者的正常组织。这项工作有几个重要的生物学意义。肿瘤生物学常常利用现有的正常组织程序。通过研究癌旁组织，结合肿瘤旁组织，我们将了解肿瘤利用哪些正常程序进行进展，这些途径可能是可靶向的。非裔美国女性的正常乳腺组织富含与白人女性不同的蛋白质，非裔美国女性更容易患上基底样乳腺癌，这一观察结果有力地表明种族和癌症亚型之间存在生物学联系。差异调节基质来源蛋白在肿瘤微环境中的作用将为种族差异的生物学基础提供新的见解。弗莱明-特罗斯特合作的长期目标是了解肿瘤与微环境的相互作用及其对乳腺癌差异的影响。