The DARC side of Breast Cancer

项目摘要 TNBC可以说是最致命的BRCA亚型，在绝经前患病率较高 在妇女和非洲裔妇女中也是如此。我们知道，TNBC患病率和 糟糕的治疗选择可能是非洲死亡率持续较高的一个原因 在美国，美国人与欧洲人相比。然而，我们已经证明，在 非洲裔美国人，BRCA存活率的差异在TNBC类别中更加明显 与ER阳性组比较。这些数据表明，独特的机制正在运行 无论是在肿瘤生物学方面还是在非洲裔妇女的宿主反应方面。古老的和非洲的- 特异性FY等位基因改变非典型趋化因子受体DARC/ACKR1的调节 组织特有的时尚超越了先前描述的RBC表型。这意味着 DARC/ACKR1在这些祖先群体中的各种改变的表型中，特别是与它相关的 趋化因子的调控。该项目将检验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，以及 由于非洲特有的FY等位基因导致血细胞上缺乏DARC表达 改变循环中的趋化因子水平，改变肿瘤微环境，增强肿瘤 攻击性。具体地说，我们将；1-确定DARC肿瘤表达是否与 非裔美国人和非裔美国人BRCA试点队列中的血统和改变的宿主免疫反应 欧裔美国人和2-确定骨髓来源(BMD)血液中是否存在DARC缺失 使用预先存在的转基因C3-细胞改变趋化因子谱和肿瘤免疫反应 1Tag BRCA和AckR1-/-小鼠。

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.