Roles of Semaphorin Signaling in Breast Cancer Racial Disparities

信号蛋白信号传导在乳腺癌种族差异中的作用

• 批准号: 8972564
• 负责人: KAI JIAO
• 金额: $ 19.18万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8972564
• 关键词: Abbreviations; Accounting; Address; Affect; African American; American; Basic Cancer Research; Bioinformatics; Biological; Biological Assay; Biological Factors; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Breast cancer metastasis; Cancer Etiology; Cells; Cessation of life; Data Set; Development; Diagnosis; Diagnostic Neoplasm Staging; Distant; ERBB2 gene; Epigenetic Process; Estrogen Receptor Status; Exploratory/Developmental Grant; Family; Fluorescent in Situ Hybridization; Foundations; Gene Expression; Genetic; Goals; Grant; Immunohistochemistry; In Vitro; Knock-out; Literature; MDA MB 231; Malignant - descriptor; Mediating; Molecular; Molecular Profiling; Mouse Mammary Tumor Virus; Mus; Nature; Neoplasm Metastasis; Non-Malignant; Normal tissue morphology; Outcome; Pathogenesis; Patients; Polymerase Chain Reaction; Publishing; Reporting; Repression; Reverse Transcription; Role; Sampling; Semaphorins; Signal Transduction; Signaling Molecule; Societal Factors; Technology; Testing; The Cancer Genome Atlas; Therapeutic; Time; Tissues; Transgenic Mice; Transplantation; Tumor stage; Woman; Work; Xenograft procedure; base; cancer cell; cancer diagnosis; cancer health disparity; caucasian American; clinical application; differential expression; early onset; in vivo; laser capture microdissection; malignant breast neoplasm; member; migration; mortality; mouse model; novel; novel diagnostics; overexpression; programs; public health relevance; pyrosequencing; racial disparity; receptor; research study; tool; triple-negative invasive breast carcinoma; tumor

 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.

 描述（由适用提供）：乳腺癌（BC）是美国女性诊断出的第二大癌症，也是女性癌症死亡的第二大原因。与高加索美国人（CA）妇女相比，非裔美国人（AA）妇女表现出较早的卑诗省发作，更有可能在表现时被诊断为卑诗省的转移性类型，并且死亡率明显更高。我们的长期目标是揭示BC结果中种族分布的生物学因素，从而有助于开发新的临床应用以消除这种分布。介导BC种族分布的生物学因素在很大程度上尚不清楚。我们使用来自TCGA（NCI）的数据集进行了生物信息学分析，并意外地发现，来自AA女性的BC组织中的SEMA6D表达明显低于CA女性。 SEMA6D的低表达水平与卑诗省患者的存活不良显着相关，并且对于三重阴性受体状态的患者（ER，PR和HER2）的关联更为显着。为了进一步支持我们的初步发现，与正常组织相比，BC组织中NCBI GEO的多个数据集证实，SEMA6D的表达显着降低。我们最初的功能分析表明，SEMA6D在体外和体内都抑制BC细胞转移。 SEMA6D是信号分子的信号素家族的成员，其在BC发病机理中的功能从未在文献中报道。基于我们的生物信息学和功能分析的结果，我们假设SEMA6D抑制BC转移，而SEMA6D的差异表达是AA与CA患者观察到的结果差异的灾难性因素。我们最初将通过AIM 1的以下两个目标来检验我们的假设；我们将确定抑制BC转移中SEMA6D的体内活性。在AIM 2中，我们将表征在AA与CA患者中观察到的SEMA6D差异表达的潜在机制。在这项研究中，我们将首次研究SEMA6D在抑制BC转移中的作用。这项研究代表了第一个将信号素信号传导与BC种族差异联系起来的研究。完成这项研究将为理解卑诗省种族分布的生物学基础提供关键集群，并将促进开发新颖的诊断/治疗方法以消除这种分布。我们的初步研究为我们的中心假设奠定了坚实的基础，并证明我们已经为拟议工作建立了必要的工具。拟议研究的紧密关注性质将使我们能够在这笔赠款的时间内解决这些问题。