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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

基本信息

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
项目类别：
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

项目摘要

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