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: 9110916
• 负责人: KAI JIAO
• 金额: $ 15.99万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110916
• 关键词: 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; Health; Immunohistochemistry; In Vitro; Knock-out; Literature; MDA MB 231; MDA-MB-468; 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; 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（由申请人提供）：乳腺癌（BC）是美国女性中第二常见的癌症，也是女性癌症死亡的第二大原因。乳腺癌发病较早，在就诊时更有可能被诊断为转移性乳腺癌，并且死亡率显着较高。我们的长期目标是揭示乳腺癌结果中种族差异背后的生物学因素，从而促进乳腺癌的发展。开发新的临床应用为了消除这种差异，我们使用 TCGA (NCI) 的数据集进行了生物信息学分析，结果发现 AA 女性的 BC 组织中的 SEMA6D 表达显着低于 CA 女性。 SEMA6D 的低表达水平与 BC 患者的不良生存率显着相关，并且对于三阴性受体状态（ER、PR 和 HER2）的患者，这种关联更为显着。 NCBI GEO 的多个数据集证实，与正常组织相比，SEMA6D 的表达在 BC 组织中显着降低。我们最初的功能测定表明，SEMA6D 在体外和体内均抑制 BC 细胞转移。及其在 BC 发病机制中的功能从未在文献中报道过。根据我们的生物信息学和功能分析的结果，我们发现 SEMA6D 抑制 BC 转移和差异表达。 SEMA6D 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检验我们的假设：在目标 1 中，我们将确定 SEMA6D 抑制 BC 转移的体内活性。描述了 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。这项研究首次将 Semaphorin 信号传导与 BC 种族差异联系起来。完成这项研究将为了解 BC 种族差异的生物学基础提供重要线索，并将促进新的诊断/治疗方法的开发，以消除这种差异。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的工作建立了必要的工具。拟议研究的紧密针对性将使我们能够在这笔拨款的时间内解决这些问题。