Triple Negative Breast Cancer: Novel Biomarkers and Therapeutic Strategies

三阴性乳腺癌：新型生物标志物和治疗策略

基本信息

批准号：
8511819
负责人：
JAMBOOR K. VISHWANATHA
金额：
$ 16.64万
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：
2013
资助国家：
美国
起止时间：
2013-07-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8511819
关键词：
ANXA2 gene Accounting Actins Affect African American American Annexins Apoptotic Awareness Biological Markers Blood specimen Breast Cancer Cell Breast Cancer Detection Breast Cancer Prevention Cancer Cell Growth Cancer Patient Cell Proliferation Cessation of life Cleaved cell Clinical Conditioned Culture Media Cytoskeletal Proteins Development Diagnosis Diagnostic Down-Regulation ERBB2 gene Education Epidermal Growth Factor Receptor Estrogen Receptors Ethnic Origin Ethnic group Extracellular Matrix Fright Genes Goals Health education Healthcare Systems Human Incidence Instruction Investigation Knock-out Knowledge Lead Malignant Neoplasms Mammary Neoplasms Mediating Mediator of activation protein Modality Molecular Monoclonal Antibodies Negative Finding Outreach Research Pathway interactions Patients Peptides Plasminogen Population Populations at Risk Prevention program Primary Prevention Progesterone Receptors Prognostic Marker Property Proteins Public Health Race Research Research Project Grants Resistance Roche brand of trastuzumab Role Signal Pathway Signal Transduction Signaling Molecule Small Interfering RNA Specimen Staging Staining method Stains Surface Systemic Therapy Testing Texas Therapeutic Tissue Sample Tissues Transcriptional Regulation Treatment Protocols Woman Women&apos s Group Work alternative treatment anticancer research autocrine base cancer cell carcinogenesis cell motility cellular transduction chemotherapeutic agent chemotherapy combat community based participatory research expectation experience health disparity high risk malignant breast neoplasm migration minority health mortality neoplastic cell new therapeutic target novel overexpression prognostic racial and ethnic small hairpin RNA therapeutic target tool triple-negative invasive breast carcinoma tumor

项目摘要

African-American women are disproportionately affected by triple negative breast cancer (TNBC), a form of breast cancer that does not express the three widely used biomarkers and therapeutic targets, namely Her-2, estrogen receptor and progesterone receptor. Consequently, these women do not benefit from the novel therapies (eg., Herceptin therapy) targeting the three biomarkers. TNBC are very aggressive, resulting in higher mortality rate in African-American women than women in other population. While TNBC is initially sensitive to chemotherapy, these women develop chemoresistance with no alternative treatment regimen available. Thus, there is a critical need to identify novel biomarkers for TNBC and develop specific therapeutic strategies to combat this health disparity. In preliminary studies, we have identified annexin A2 as a putative biomarker for TNBC. When Her-2 is negative, we find annexin A2 expression to be significantly increased, and conversely when Her-2 is overexpressed, annexin A2 expression is decreased. We hypothesize that AnxA2 overexpression accounts for the disproportionate occurrence of TNBC in African American women, and that AnxA2 is a useful biomarker and therapeutic target for TNBC. We will test this hypothesis through the following specific aims: 1) To integrate TNBC as a focus of education in an ongoing primary prevention program targeting high nsk AA women, 2) To establish the correlation of AnxA2 expression with poor pathological, prognostic variables and ethnicity in TNBC patients, and validate AnxA2 as a diagnostic biomarker for TNBC patients. 3) To delineate AnxA2-EGFR mediated downstream signaling pathway which regulates cancer cell proliferation, migration and invasion in TNBC, and 4) To establish AnxA2 as a therapeutic target in triple negative breast cancer. Our expectation is that successful completion of the proposed work will identify a specific biomarker for TNBC that could be targeted by novel therapeutic strategies. The proposed investigations will help in understanding the role of AnxA2 expression in the incidence of TNBC in various ethnic groups.

非裔美国妇女受到三重阴性乳腺癌（TNBC）的影响不成比例不表达三种广泛使用的生物标志物和治疗靶标的乳腺癌，即 HER-2，雌激素受体和孕酮受体。因此，这些妇女并没有从中受益针对三种生物标志物的新型疗法（例如，赫斯汀疗法）。 TNBC非常激进，由此产生非裔美国妇女的死亡率高于其他人口的妇女。而TNBC最初是对化学疗法敏感，这些女性发展化学疗法，没有其他治疗方案可用的。因此，迫切需要确定TNBC的新型生物标志物并开发特定的生物标志物应对这种健康差异的治疗策略。在初步研究中，我们已经确定了Annexin A2 作为TNBC的推定生物标志物。当HER-2为负时，我们发现膜联蛋白A2表达显着增加，相反，当HER-2过表达时，膜联蛋白A2表达降低。我们假设Anxa2的过表达解释了非洲TNBC的不成比例美国妇女，而Anxa2是TNBC的有用的生物标志物和治疗靶标。我们将测试这个通过以下特定目的进行假设：1）将TNBC整合为持续的教育重点针对高NSK AA妇女的初级预防计划，2）建立Anxa2的相关性 TNBC患者的病理，预后变量和种族的表达不良，并验证Anxa2 作为TNBC患者的诊断生物标志物。 3）描绘Anxa2-EGFR介导的下游信号传导调节TNBC中癌细胞增殖，迁移和侵袭的途径，以及4） AnxA2是三重阴性乳腺癌的治疗靶标。我们的期望是，成功完成拟议的工作将确定特定的生物标志物可以由新型治疗策略来针对的TNBC。拟议的调查将有助于了解Anxa2表达在TNBC发病率中的作用。