Roles of Semaphorin Signaling in Breast Cancer Racial Disparities

 描述（由申请人提供）：乳腺癌（BC）是美国妇女诊断的第二大常见癌症，也是妇女癌症死亡的第二大原因。与白人美国（CA）女性相比，非洲裔美国（AA）女性显示出更早的BC发作，更有可能在就诊时被诊断为转移性BC，并且具有显著更高的死亡率。我们的长期目标是揭示BC结果中种族差异的生物学因素，从而促进新的临床应用的发展，以消除这种差异。介导BC种族差异的生物因素在很大程度上仍然未知。我们使用来自TCGA（NCI）的数据集进行了生物信息学分析，并且意外地鉴定出来自AA女性的BC组织中的SEMA 6D表达显著低于CA女性。SEMA 6D的低表达水平与BC患者的不良存活率显著相关，并且对于具有三阴性受体状态（ER、PR和HER 2）的患者，该关联更显著。为了进一步支持我们的初步发现，对来自NCBI GEO的多个数据集的检查证实，与正常组织相比，SEMA 6D的表达在BC组织中显著降低。我们最初的功能测定表明，SEMA 6D在体外和体内都抑制BC细胞转移。SEMA 6D是信号分子Semaphorin家族的成员，其在BC发病机制中的功能在文献中从未报道。基于我们的生物信息学和功能分析的结果，我们假设SEMA 6D抑制BC转移，并且SEMA 6D的差异表达是AA与CA患者中观察到的结果差异的致病因素。我们将首先通过以下两个目标来测试我们的假设：在目标1中，我们将确定SEMA 6D在抑制BC转移中的体内活性。在目标2中，我们将描述AA与CA患者中观察到的SEMA 6D差异表达的潜在机制。在这项研究中，我们将首次研究SEMA 6D在抑制BC转移中的作用。这项研究首次将脑信号蛋白信号与BC种族差异联系起来。完成这项研究将提供重要的线索，了解生物学基础的种族差异在不列颠哥伦比亚省，并将促进新的诊断/治疗方法的发展，以消除这种差异。我们的初步研究为我们的中心假设提供了坚实的基础，并表明我们已经为拟议的工作建立了必要的工具。拟议研究的集中性将使我们能够在这笔赠款的时间范围内解决这些问题。

 DESCRIPTION (provided by applicant): Breast cancer (BC) is the second most common cancer diagnosed in American women and is also the second leading cause of cancer death in women. Compared to Caucasian American (CA) women, African American (AA) women display earlier onset of BC, are more likely to be diagnosed with metastatic types of BC at the time of presentation, and have a significantly higher mortality rate. Our long term goal is to reveal the biological factors underlying racial disparities in BC outcomes and thereby facilitate development of novel clinical applications to eliminate such disparities. The biological factors that mediate BC racial disparities remain largely unknown. We performed a bioinformatic analysis using a dataset from TCGA (NCI) and unexpectedly identified that SEMA6D expression in BC tissues from AA women was significantly lower than in CA women. The low expression level of SEMA6D correlates significantly with poor survival of BC patients, and the association is more dramatic for patients with triple negative receptor status (ER, PR and HER2). In further support of our initial finding, examination of multiple datasets from NCBI GEO confirmed that expression of SEMA6D is significantly reduced in BC tissues compared to normal tissues. Our initial functional assay indicated that SEMA6D represses BC cell metastasis both in vitro and in vivo. SEMA6D is a member of the Semaphorin family of signaling molecules and its functions in BC pathogenesis have never been reported in the literature. Based on results from both our bioinformatic and functional analyses, we hypothesize that SEMA6D inhibits BC metastasis and differential expression of SEMA6D is a causative factor for outcome disparities observed in AA versus CA patients. We will initially test our hypothesis through the following two aims In Aim 1; we will determine the in vivo activity of SEMA6D in repressing BC metastasis. In Aim 2, we will characterize the potential mechanism for the differential expression of SEMA6D observed in AA versus CA patients. In this study, we will examine for the first time the role of SEMA6D in repressing BC metastasis. This study represents the first to connect Semaphorin signaling with BC racial disparities. Accomplishing this study will provide crucial clues for understanding the biological basis for racial disparities in BC and will facilitate development of novel diagnostic/therapeutic approaches to eliminate such disparities. Our preliminary studies provide a strong foundation for our central hypothesis and demonstrate that we have established the necessary tools for the proposed work. The tightly focused nature of the proposed studies will allow us to address these questions within the time-frame of this grant.