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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

基本信息

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
项目类别：
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

项目摘要

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.

专题摘要/摘要-专题一