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: 10708080
• 负责人: Kevin Peter Williams
• 金额: $ 24.85万
• 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/10708080
• 关键词: Anthropology; Automobile Driving; Biological; Biological Markers; Black race; Breast; 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; Disparity; 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; Infiltration; Lesion; Location; Malignant Neoplasms; Measures; Mediating; Mediator; 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; Transfection; 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; outcome disparities; patient subsets; prognostic; programs; promoter; receptor; social; spatial relationship; stemness; 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 女性。患者预后的推动力是癌症诊断和可用治疗选择的类型。 我们专注于两个高度侵略性的BC亚型：马酮受体负基碱性乳腺癌（BLBC） 以及研究不足和致命的炎症性乳腺癌（IBC）。黑人妇女出现较高的比率 BLBC与白人妇女，并且由于缺乏高效的疗法，生存率很差。 NCI指出IBC是 在年轻的黑人妇女中更常见和诊断，通常是同性恋受体阴性。显然需要 要对这些致命的BC进行更多的高级研究及其共同主题，对于患者的生存至关重要 并了解不同的结果。许多研究评估了黑人妇女和白人BC的差异 妇女检查肿瘤特征；但是，导致这种差异的病因学因素仍然很差。 我们的数据表明，黑人妇女具有独特的免疫和基质细胞浸润和蛋白质水平的改变 正常的乳房和肿瘤微环境。我们的目标是确定涉及进展的机制 由于取消现场的基质作用，黑人妇女的侵略性，转移性BC 病变。 AIM 1利用我们已发表的研究和试点表达数据集详细介绍种族和肿瘤 - 亚型特异性基质相互作用确定了聚焦途径，肝细胞生长因子（HGF）信号传导。 我们建议使用开创性工具来识别细胞类型的特定来源，级别和空间取向 我们的信号通路分子在异质性肿瘤中。我们将比较这些复杂数据 黑白BLBC和IBC肿瘤。接下来，我们将测量HGF功能的表达 多态性，在黑人妇女中高度表达。这种遗传差异可能导致显着的 较差的预后和存活率。这些数据将定义可能从中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。 AIM 2然后评估新型免疫 对IBC发病机理的签名贡献，并测试其与HGF信号，种族和较差的关联 结果。 AIM 3将使用专注于放松管制的DNA修复机的强大实验研究 阐明HGF多晶型物的机械细节及其对HGF过表达的后果。这些 数据将极大地有助于克服我们对这种高度侵略性IBC的了解，并提供 一个强大的签名，以确定有发展IBC风险的人。我们的团队建立了研究合作伙伴关系 提供了包括卡罗来纳州乳腺癌研究在内的资源的访问：一项独特的流行病学研究 种族多样的患者。通过研究具有不同免疫/伤口愈合特征的BLBC以及 理解的IBC，在导致不同结果的程序中的相似之处可能会出现。这些途径会 很可能是针对性的。我们合作的长期目标是了解肿瘤微环境 相互作用及其对卑诗省分布的影响，以产生被翻译的发现并导致新的生物标志物。