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

描述(由申请人提供)：绝经前的非裔美国女性与高加索裔美国患者相比，患有基底细胞样三阴性乳腺癌的比例更高。目前，还没有有效的分子疗法来治疗这种高度侵袭性的癌症，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都检查了肿瘤的特征，然而，导致这种差异的病因仍未确定。我们的初步数据表明，HGF在乳腺癌进展以及非裔美国人和高加索人患者之间的差异中发挥了作用。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，并利用该特征来评估HGF途径在非裔美国人和高加索人患者中的表达以及根据乳腺癌亚型的表达。目的2将使用来自非裔美国人和高加索患者的原代细胞系来评估成纤维细胞HGF表达的变化对癌细胞表型的影响，包括增殖和运动能力的测定。因此，我们的主要目标是确定绝经前非裔美国人发生侵袭性、转移性乳腺癌的机制，这是癌变部位间质效应的结果。我们的团队已经建立了研究伙伴关系，提供了访问资源的途径，包括正常乳房研究：一项对北卡罗来纳大学医院不同种族患者的正常组织进行的独特流行病学研究。这项工作有几个重要的生物学意义。肿瘤生物学经常利用现有的正常组织程序。通过研究癌旁组织，结合癌旁组织，我们将了解肿瘤利用哪些正常程序进行进展，这些途径可能是有针对性的。观察到，非裔美国女性的正常乳房组织富含与高加索女性不同的项目中的蛋白质，而且非裔美国女性更容易患上基底细胞样乳腺癌，这有力地表明了种族和癌症亚型之间的生物学联系。差异调控的基质衍生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-微环境的相互作用及其对乳腺癌差异的影响。

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.