Immune Microenvironments and Hepatocyte Growth Factor Signaling Interactions in Breast Cancer Disparities

乳腺癌差异中的免疫微环境和肝细胞生长因子信号传导相互作用

• 批准号: 10556581
• 负责人: Kevin Peter Williams
• 金额: $ 25.52万
• 依托单位: NORTH CAROLINA CENTRAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556581
• 关键词: Anthropology; Automobile Driving; Biological; Biological Markers; Black race; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer cell line; Breast Carcinoma; Cancer Prognosis; Cancerous; Cell Communication; Cells; Cessation of life; Characteristics; Clinical; Collaborations; DNA Repair; Data; Data Set; Deoxyadenosines; Detection; Diagnosis; Elements; Etiology; Frequencies; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genetic Polymorphism; Genomic Instability; Goals; Growth Factor Gene; Growth Factor Overexpression; HGF gene; Health Disparities Research; Immune; Immunohistochemistry; In Vitro; Lead; Lesion; Location; Mammary Neoplasms; Measures; Mediating; Mediator of activation protein; Metastatic breast cancer; Methods; Molecular; Mus; Mutagenesis; Mutate; Mutation; Neoplasm Metastasis; Oncogenic; Outcome; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Polymorph; Population Heterogeneity; Prognosis; Promoter Regions; Proteins; Publishing; RNA; Race; Research; Resources; Risk; Role; Sampling; Sampling Studies; Signal Pathway; Signal Transduction; Site; Source; Space Perception; Stromal Cells; Survival Rate; Techniques; Testing; Therapeutic; Tissues; Translating; Tumor Subtype; Woman; age related; aggressive breast cancer; black women; breast cancer progression; cancer diagnosis; cancer health disparity; cancer subtypes; cancer type; cell type; comparative; complex data; defined contribution; digital; driving force; effective therapy; epidemiology study; ethnic diversity; experimental study; genetic signature; hormone receptor-negative; immunological status; in vivo; inflammatory breast cancer; innovation; malignant breast neoplasm; mortality; nano-string; neoplastic cell; novel; novel strategies; novel therapeutic intervention; patient subsets; prognostic; programs; promoter; receptor; social; spatial relationship; stemness; targeted biomarker; targeted treatment; tool; transcriptome sequencing; tumor; tumor growth; tumor heterogeneity; tumor microenvironment; tumor-immune system interactions; tumorigenesis; wound healing

PROJECT SUMMARY / ABSTRACT – Project 1 Black women suffer disproportionately from higher mortality rates of breast cancers (BC) compared to White women. A driving force in patient outcome is the type of cancer diagnosis and the available treatment options. We focus on two highly aggressive BC subtypes: the hormone receptor negative basal-like breast cancer (BLBC) and the under-studied and deadly inflammatory breast cancer (IBC). Black women present with higher rates of BLBC vs. White women, and since highly effective therapies are lacking, survival is poor. The NCI states IBC is more common and diagnosed in younger Black women, and is often hormone receptor negative. Clearly a need to conduct more advanced studies into these lethal BCs, and their common themes, is critical for patient survival and understanding disparate outcomes. Many studies assessing differences in BCs in Black women and White women examine tumor characteristics; however, etiologic factors that lead to this disparity remain poorly defined. Our data show Black women have unique immune and stromal cell infiltrate and altered protein levels within normal breast and tumor microenvironments. Our objective is to identify mechanisms involved in the progression of aggressive, metastatic BC in Black women as a consequence of stromal effects at the site of the cancerous lesion. Aim 1 takes advantage of our published studies and pilot expression datasets detailing race and tumor- subtype specific stromal interactions that identified a focused pathway, hepatocyte growth factor (HGF) signaling. We propose to use groundbreaking tools to identify the cell-type specific source, levels, and spatial orientation of our signaling pathway molecules within heterogeneous tumors. We will compare these complex data between Black and White BLBC and IBC tumors. Next, we will measure the expression of an HGF functional polymorphism, which is highly expressed in Black women. This genetic difference likely results in a significantly poorer prognosis and survival rate. These data will define subsets of patients who may benefit the most from HGF/MET therapeutics, as this has been a limiting clinical setback. Aim 2 will then evaluate novel immune signature contributions to IBC pathogenesis, and test their association with HGF signaling, race, and poorer outcomes. Aim 3 will use robust experimental studies focused on deregulated DNA repair machineries to elucidate the mechanistic details of the HGF polymorph and its consequence of HGF over-expression. These data will significantly contribute to overcoming our lack of understanding of this highly aggressive IBC and provide a robust signature to identify those at risk for developing IBC. Our team has established research partnerships that provide access to resources including the Carolina Breast Cancer Study: a unique epidemiologic study from ethnically diverse patients. By studying BLBC that has distinct immune/wound healing signatures together with the understudied IBCs, parallels in programs that lead to disparate outcomes may emerge. These pathways will very likely be targetable. The long-term goal of our collaboration is to understand tumor microenvironment interactions and their influence on BC disparities to yield discoveries to be translated and lead to new biomarkers.

项目摘要/摘要--项目1 与白人相比，黑人女性的乳腺癌死亡率(BC)更高，这一比例更高 女人。影响患者预后的一个驱动力是癌症诊断的类型和可用的治疗选择。 我们关注两种高度侵袭性的BC亚型：激素受体阴性的基底细胞样乳腺癌(BLBC)。 以及研究不足的致命性炎症性乳腺癌(IBC)。黑人女性的患病率更高 BLBC与白人女性相比，由于缺乏高效的治疗方法，存活率很低。NCI表示，IBC是 在年轻的黑人女性中更为常见和确诊，通常激素受体为阴性。显然，这是一种需要 对这些致命的BCS及其共同主题进行更深入的研究，对患者的生存至关重要 以及理解不同的结果。许多研究评估黑人女性和白人的BCS差异 女性检查肿瘤特征；然而，导致这种差异的病因因素仍不明确。 我们的数据显示，黑人女性体内有独特的免疫和基质细胞渗透和改变的蛋白质水平 正常的乳房和肿瘤微环境。我们的目标是找出与这一进程有关的机制 癌症部位间质效应对黑人女性侵袭性、转移性BC的影响 损伤。Aim 1利用了我们发表的研究和试点表达数据集，详细描述了种族和肿瘤- 亚型特定的间质相互作用，确定了一条聚焦的途径，肝细胞生长因子(HGF)信号。 我们建议使用开创性的工具来识别特定细胞类型的源、级别和空间方向 我们的信号通路分子在异质肿瘤中的作用。我们将比较这些复杂的数据和 黑白BLBC和IBC肿瘤。接下来，我们将测量HGF功能的表达 多态，这在黑人女性中高度表达。这种遗传差异可能导致显著的 预后和生存率较差。这些数据将定义可能受益最大的患者子集 HGF/MET疗法，因为这是一个有限的临床挫折。然后，AIM 2将评估新的免疫 IBC发病机制的标志性贡献，并测试它们与HGF信号、RACE和较差的关联 结果。Aim 3将使用专注于解除管制的DNA修复机制的强大实验研究来 阐明HGF多态的机制细节及其导致HGF过度表达的后果。这些 数据将大大有助于克服我们对这一高度激进的IBC的缺乏了解，并提供 一个强大的签名，以确定哪些人处于发展IBC的风险之中。我们的团队已经建立了研究伙伴关系 提供了包括卡罗莱纳乳腺癌研究在内的资源：一项来自 不同种族的病人。通过研究具有明显免疫/伤口愈合特征的BLBC 研究不足的IBCs，可能会出现导致不同结果的项目中的相似之处。这些途径将 很可能是有针对性的。我们合作的长期目标是了解肿瘤微环境 相互作用及其对BC差异的影响，以产生需要翻译的发现并导致新的生物标记物。