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

• 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
• 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' 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

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.

非洲裔美国妇女不成比例地受到三阴性乳腺癌（TNBC）的影响，这是一种 不表达三种广泛使用的生物标志物和治疗靶点的乳腺癌，即 HER-2、雌激素受体和孕激素受体。因此，这些妇女没有从 新疗法（例如，赫赛汀疗法）靶向三种生物标志物。TNBC非常具有侵略性， 非裔美国妇女的死亡率高于其他人口中的妇女。虽然TNBC最初是 对化疗敏感，这些妇女在没有替代治疗方案的情况下产生耐药性 available.因此，迫切需要鉴定用于TNBC的新生物标志物并开发特异性生物标志物。 治疗策略来消除这种健康差距。在初步研究中，我们已经确定了膜联蛋白A2 作为TNBC的推定生物标志物。当Her-2阴性时，我们发现膜联蛋白A2表达显著增加， 相反，当Her-2过表达时，膜联蛋白A2表达降低。 我们假设AnxA 2过表达是非洲人TNBC不成比例发生的原因。 AnxA 2是TNBC的有用生物标志物和治疗靶点。我们将测试这个 （1）将TNBC作为一个教育重点纳入正在进行的 针对高nsk AA妇女的一级预防计划，2）建立AnxA 2 在TNBC患者中，AnxA 2表达与病理学、预后变量和种族相关，并验证AnxA 2 作为TNBC患者的诊断生物标志物。3)描述AnxA 2-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）建立 AnxA 2作为三阴性乳腺癌的治疗靶点 我们的期望是，成功完成拟议的工作将确定一个特定的生物标志物， TNBC可以通过新的治疗策略靶向。拟议的调查将有助于 了解AnxA 2表达在不同种族TNBC发病率中的作用。