The DARC side of Breast Cancer

乳腺癌的 DARC 方面

基本信息

批准号：
9301144
负责人：
Melissa B Davis
金额：
$ 3.45万
依托单位：
UNIVERSITY OF GEORGIA
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：
2017-05-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9301144
关键词：
Address African African American Aggressive behavior Alleles American Antigen Receptors B-Lymphocytes Biological Biological Assay Blood Cells Blood Circulation Bone Marrow Cells Cancer Prognosis Categories Cells Data Development Diagnosis ERBB2 gene Epigenetic Process Estrogen Receptors Estrogen receptor positive Etiology European Flow Cytometry Future Gene Amplification Genetic Genetic Models for Cancer Goals High Prevalence Human Immune Immune response Immunohistochemistry Immunology Individual Infiltration Knock-out Mammary Neoplasms Measures Mediating Mus Outcome Patients Pattern Phenotype Population Premenopause Prevalence Progesterone Receptors Protein Isoforms Race Radiation therapy Recruitment Activity Regulation Role Side Survival Rate T-Lymphocyte Testing Tissues Transcript Transgenic Mice Transgenic Organisms Tumor Biology Woman Work base breast cancer survival cancer subtypes cell type chemokine chemokine receptor chemotherapy cohort human subject immunoregulation in vivo in vivo Model insight lifetime risk malignant breast neoplasm monocyte mortality mouse model neoplastic cell neutrophil novel null mutation personalized medicine prognostic targeted treatment therapeutic target tool treatment response triple-negative invasive breast carcinoma tumor tumor microenvironment tumor progression tumorigenesis

项目摘要

Project Summary TNBC is arguably the most deadly BrCa subtype with higher prevalence in pre-menopausal women and in women of African descent. We know that the combined TNBC prevalence and poor treatment options are a likely cause of persistently higher mortality rates in African Americans compared to European Americans in the US. However, we have shown that within African Americans, disparities in BrCa survival are more pronounced within the TNBC category compared to the ER positive groups. These data indicate that unique mechanisms are operating in either tumor biology or host response in women of African descent. The ancient and African- specific Fy- allele alters the regulation of DARC/ACKR1, an atypical chemokine receptor, in a tissue-specific fashion beyond the previously described RBC phenotype. This implicates DARC/ACKR1 in various altered phenotypes in these ancestry groups, specifically as it relates to chemokine regulation. This project will test the hypothesis that DARC expression in tumor cells alters tissue chemokine levels to modify the host immune response to tumorigenesis, and that absence of DARC expression on blood cells as a result of the African-specific Fy- allele alters circulating chemokine levels, altering the tumor microenvironment and enhancing tumor aggression. Specifically we will; 1- Determine if DARC tumor expression associates with ancestry and altered host immune responses in a pilot BrCa cohort of African Americans and European Americans and 2- Determine if loss of DARC on bone-marrow-derived (bmd) blood cells alters chemokine profiles and tumor immune response, using pre-existing transgenic C3- 1Tag BrCa and AckR1-/- mice.

项目摘要 TNBC可以说是最致命的BRCA子类型，在绝经前的患病率较高妇女和非洲血统的妇女。我们知道，TNBC的综合患病率和治疗选择不佳可能是非洲持续更高死亡率的原因美国人与美国的欧洲人相比。但是，我们已经证明了这一点非裔美国人，BRCA生存的差异在TNBC类别中更为明显与ER阳性组相比。这些数据表明独特的机制正在运行在肿瘤生物学或非洲血统妇女中的宿主反应中。古代和非洲 - 特定的fy-等位基因改变了在A中的非典型趋化因子受体DARC/ACKR1的调节除了先前描述的RBC表型之外，组织特异性的方式。这意味着在这些祖先的各种改变表型中的darc/ackr1，特别是因为它与之相关趋化因子调节。该项目将测试DARC在肿瘤中表达的假设细胞改变组织趋化因子水平，以改变宿主对肿瘤发生的免疫反应，并由于非洲特异性的FY-等位基因，血细胞上没有DARC表达改变循环趋化因子水平，改变肿瘤微环境并增强肿瘤侵略。特别是我们会的； 1-确定DARC肿瘤表达是否与在非裔美国人的BRCA队列中，祖先和改变了宿主的免疫反应欧洲人和2-确定在骨髓衍生的（BMD）血液中失去了DARC是否丧失细胞使用预先存在的转基因C3-来改变趋化因子谱和肿瘤免疫反应 1TAG BRCA和ACKR1 - / - 小鼠。