Triple Negative Breast Cancer: Novel Biomarkers and Therapeutic Strategies

非裔美国女性受三重阴性乳腺癌(TNBC)的影响不成比例，TNBC是一种 乳腺癌不表达三个广泛使用的生物标记物和治疗靶点，即 HER-2、雌激素受体和孕激素受体。因此，这些妇女不会从 针对这三个生物标志物的新疗法(如赫赛汀疗法)。TNBC非常具有侵略性，因此 非洲裔美国女性的死亡率高于其他人口中的女性。而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化疗耐药性 可用。因此，迫切需要为TNBC确定新的生物标记物，并开发特异性的 消除这种健康差距的治疗策略。在初步研究中，我们发现了膜联蛋白A2 作为TNBC的推定生物标志物。当HER-2为阴性时，我们发现Annexin A2的表达显著 相反，当HER-2过表达时，Annexin A2的表达减少。 我们假设AnxA2的过度表达是非洲TNBC不成比例发生的原因 AnxA2是TNBC的有用生物标记物和治疗靶点。我们将对此进行测试 通过以下具体目标提出假设：1)将TNBC作为正在进行的教育的重点 针对高NSK再生障碍性贫血妇女的一级预防方案，2)建立AnxA2的相关性 TNBC患者中病理、预后变量和种族不良的表达，并验证AnxA2 作为诊断TNBC患者的生物标志物。3)AnxA2-EGFR介导的下游信号转导通路 调控癌细胞在TNBC中增殖、迁移和侵袭的途径，以及4)建立 AnxA2作为三阴性乳腺癌的治疗靶点。 我们期望，拟议工作的成功完成将确定一个特定的生物标记物 可以被新的治疗策略作为靶点的TNBC。拟议的调查将有助于 了解AnxA2表达在不同民族TNBC发病中的作用。

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.