Investigating serum exosomal annexin A2 in promoting aggressive TNBC in African American women

研究血清外泌体膜联蛋白 A2 在促进非洲裔美国女性侵袭性 TNBC 中的作用

• 批准号: 9388064
• 负责人: JAMBOOR K. VISHWANATHA
• 金额: $ 38.05万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9388064
• 关键词: Actins; Address; Adhesions; Affect; African; African American; Annexins; Biological Assay; Blinded; Brain; Breast Cancer Patient; Breast Cancer Treatment; Breast cancer metastasis; Cancer Patient; Caucasians; Cell Line; Cells; Clinical; Communication; Data; Dependence; Detection; Diagnosis; Disease; Distant; European; Extracellular Matrix; Ghana; Goals; Growth Factor; Hospitals; Immunologics; Lead; Literature; Location; Lung; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Molecular; Mus; Neoplasm Metastasis; Nigeria; Norway; Nucleic Acids; Organ; Outcome; Pathogenesis; Patients; Peptides; Plasminogen; Population; Proteins; Proteomics; Publishing; Research; Role; Serum; Signal Transduction; Site; Stromal Cells; Stromal Neoplasm; Therapeutic; Time; Tissues; Tropism; Tumor-Derived; United Kingdom; Vesicle; Woman; angiogenesis; bone; cancer cell; caucasian American; cell motility; clinical translation; cytokine; exosome; extracellular; health disparity; improved; in vivo; innovation; intercellular communication; loss of function; mortality; neoplastic cell; novel; novel therapeutics; outcome forecast; prognostic; signature molecule; small hairpin RNA; stem; targeted agent; therapeutic target; tool; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; tumorigenesis

Project Abstract Triple negative breast cancer (TNBC) affects women of African descent three times more than women of European descent. African American women with TNBC have poor survival and high mortality rates. Metastasis to distant vital organs such as bone, lung, and brain is the most devastating feature of TNBC. It is critical to investigate the molecular mechanism(s) that lead to aggressive disease in patients with TNBC so that improved therapeutic options can be developed. Emerging evidence suggests that tumor-derived exosomes are mediators of tumorigenesis and tissue-specific metastasis by contributing to the establishment of a pre- metastatic niche. Annexin A2 (AnxA2) is an often identified exosomal protein whose elevated levels are seen in TNBC patient sera and cell lines. Exosomal AnxA2 (exo-AnxA2) is more highly expressed in African American (AA) TNBC patients than in Caucasian TNBC patients resulting in reduced survival. Our recent data suggest a role for exo-AnxA2 in establishing a pre-metastatic niche which subsequently promotes breast cancer metastasis. The long-term goal of our research is to develop improved therapeutic options for aggressive TNBC that disproportionately affects AA patients. Our hypothesis for the proposed studies is that exo-AnxA2 is a determinant of the aggressiveness of TNBC metastasis and contributes to poor prognosis in AA patients with TNBC. The premise for this hypothesis stems from the literature (2, 6-9,11) and our published data indicating that exo-AnxA2 creates a pre-metastatic niche that may drive aggressive TNBC metastasis. We will address this hypothesis by the following three specific aims: Aim 1: Evaluate differences in the association of exo-AnxA2 expression with measures of disease aggressiveness among racially distinct populations. Aim 2: Determine whether exo-AnxA2 promotes aggressive TNBC metastasis. Aim 3: Determine the mechanism(s) that drives exo-AnxA2-mediated metastatic niche formation and aggressive tumors in TNBC. The impact of the proposed studies is the likely identification of a novel secreted and exosomal protein as a functional regulator of long-range communications between metastatic tumors and the target stromal microenvironment. Moreover, due to their extracellular location, secreted AnxA2 and partner proteins represent potential prognostic agents and therapeutic targets. Thus, we expect this research to open up exciting new avenues of clinical translation in metastasis detection, prognosis, and therapy for TNBC patients.

项目摘要 三阴性乳腺癌（TNBC）对非洲裔女性的影响是非洲裔女性的三倍 欧洲血统。患有 TNBC 的非裔美国女性生存率低且死亡率高。 远处重要器官（如骨、肺和脑）的转移是 TNBC 最具破坏性的特征。这是 研究导致 TNBC 患者发生侵袭性疾病的分子机制至关重要，以便 可以开发改进的治疗方案。新的证据表明肿瘤来源的外泌体 是肿瘤发生和组织特异性转移的介质，有助于建立预 转移生态位。膜联蛋白 A2 (AnxA2) 是一种经常被识别的外泌体蛋白，其水平升高 TNBC 患者血清和细胞系中。外泌体 AnxA2 (exo-AnxA2) 在非洲表达更高 美国（AA）TNBC患者比白人TNBC患者导致生存率降低。我们最近的数据 表明 exo-AnxA2 在建立转移前生态位中的作用，随后促进乳腺发育 癌症转移。我们研究的长期目标是开发改进的治疗方案 侵袭性 TNBC 对 AA 患者的影响尤为严重。我们对拟议研究的假设是 exo-AnxA2 是 TNBC 转移侵袭性的决定因素，并导致不良预后 患有 TNBC 的 AA 患者。该假设的前提源于文献 (2, 6-9,11) 和我们发表的 数据表明 exo-AnxA2 创建了一个转移前生态位，可能会驱动侵袭性 TNBC 转移。 我们将通过以下三个具体目标来解决这一假设： 目标 1：评估 exo-AnxA2 表达与不同种族之间疾病侵袭性测量的关联 人口。目标 2：确定 exo-AnxA2 是否促进侵袭性 TNBC 转移。目标 3：确定 驱动 exo-AnxA2 介导的转移性微环境形成和侵袭性肿瘤的机制 TNBC。拟议研究的影响是可能鉴定出一种新的分泌型外泌体蛋白 作为转移性肿瘤和靶基质之间远程通讯的功能调节剂 微环境。此外，由于其细胞外位置，分泌的 AnxA2 和伴侣蛋白代表 潜在的预后因素和治疗靶点。因此，我们期望这项研究能够开辟令人兴奋的新领域 TNBC 患者转移检测、预后和治疗的临床转化途径。