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: 10001985
• 负责人: JAMBOOR K. VISHWANATHA
• 金额: $ 36.71万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001985
• 关键词: Actins; Address; Adhesions; Affect; African; African American; Annexins; Biological Assay; Blinded; Brain; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Breast cancer metastasis; 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）对非洲裔妇女的影响是非洲裔妇女的三倍。 欧洲血统。患有TNBC的非裔美国妇女生存率低，死亡率高。 转移到远处的重要器官如骨、肺和脑是TNBC最具破坏性的特征。是 研究导致TNBC患者侵袭性疾病的分子机制至关重要， 可以开发改进的治疗选择。新出现的证据表明，肿瘤来源的外泌体 是肿瘤发生和组织特异性转移的介质，通过促进建立前 转移小生境膜联蛋白A2（AnxA 2）是一种经常被鉴定的外泌体蛋白， 在TNBC患者血清和细胞系中。外泌体AnxA 2（exo-AnxA 2）在非洲人中表达更高 美国（AA）TNBC患者比高加索TNBC患者的生存率低，导致生存率降低。我们最近的数据 表明exo-AnxA 2在建立转移前小生境中作用， 癌症转移我们研究的长期目标是开发更好的治疗方案， 侵袭性TNBC不成比例地影响AA患者。我们对拟议研究的假设是， exo-AnxA 2是TNBC转移侵袭性的决定因素，并导致TNBC患者预后不良。 患有TNBC的AA患者这一假设的前提来自文献（2，6- 9，11）和我们发表的 数据表明exo-AnxA 2产生转移前小生境，其可驱动侵袭性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 不同种族间exo-AnxA 2表达与疾病侵袭性的相关性 人口。目的2：确定exo-AnxA 2是否促进侵袭性TNBC转移。目标3：确定 驱动exo-AnxA 2介导的转移性小生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一种新的分泌和外泌体蛋白 作为转移性肿瘤和靶基质之间的远程通信的功能调节剂 微环境此外，由于它们的细胞外位置，分泌的AnxA 2和伴侣蛋白代表 潜在的预后剂和治疗靶点。因此，我们希望这项研究能够开辟令人兴奋的新领域。 转移检测、预后和TNBC患者治疗的临床转化途径。