The DARC side of Breast Cancer

乳腺癌的 DARC 方面

• 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
• 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

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亚型，在绝经前妇女中患病率较高。 妇女和非洲裔妇女。我们知道TNBC的患病率和 不良的治疗选择可能是非洲国家死亡率持续升高的原因。 美国人与美国的欧洲人相比。然而，我们已经表明，在 在非裔美国人中，BrCa生存率的差异在TNBC类别中更为明显 与ER阳性组相比。这些数据表明， 无论是肿瘤生物学还是宿主反应。古代和非洲- 特异性Fy-等位基因改变DARC/ACKR 1（一种非典型趋化因子受体）的调节， 组织特异性方式超出了先前描述的RBC表型。这意味着 DARC/ACKR 1在这些祖先群体中的各种改变的表型中，特别是当它涉及 到趋化因子调节。本项目将验证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应答， 由于非洲特异性Fy-等位基因导致血细胞上DARC表达的缺失， 改变循环趋化因子水平，改变肿瘤微环境，增强肿瘤细胞增殖， 侵略具体来说，我们将：1-确定DARC肿瘤表达是否与 在非裔美国人的试点BrCa队列中， 欧洲裔美国人和2-确定骨髓衍生（bmd）血液中DARC的丢失 细胞改变趋化因子谱和肿瘤免疫应答，使用预先存在的转基因C3- 1 Tag BrCa和AckR 1-/-小鼠。