Hippo signaling pathway in breast cancer disparities: a translational approach

描述(申请人提供)：尽管总体而言，欧洲裔美国人(EA)女性的乳腺癌发病率高于非裔美国人(AA)女性，但AA女性更有可能在更年轻的年龄被诊断为更具侵袭性的肿瘤，其特点是级别更高，增殖指数更高，以及缺乏雌激素(ER)和孕激素受体(PR)的表达。AA妇女也比EA妇女更有可能患有三阴性乳腺癌(TNBCs)，即ER、PR和HER2阴性。这些肿瘤预后较差，因为它们往往级别较高，对抗雌激素或抗HER2治疗不敏感，因此可供选择的治疗方法较少。乳腺癌侵袭性和发病年龄方面的种族差异的原因尚不清楚。河马途径最早是在果蝇中发现的，它通过调节细胞的生长、增殖和凋亡来控制器官的大小，所有的核心成分在哺乳动物中都得到了很好的保守。DNA高甲基化下调Hippo通路成分LATS1/2与肿瘤大小、淋巴结转移和ER/PR阴性有关。我们的初步数据还显示，河马通路成分YAP/TAZ的功能障碍激活了EGFR信号，YAP/TAZ在三阴性和高级别乳腺肿瘤中特异性增加，这两种亚型在年轻AA患者中比EA女性中更常见。基于以上证据，我们推测，在侵袭性更强的乳腺癌中，Hippo信号通路的功能障碍导致EGFR信号的异常激活，这种情况在AA女性中比EA女性中更常见。我们将在两个现有研究群体的背景下研究这一假说，有以下两个具体目标：1)确定YAP/TAZ激活的EGFR信号通路是否有助于TNBC的发生；2)使用乳腺癌肿瘤标本研究YAP/TAZ激活的EGFR在AA和EA女性之间的差异。这种方法是创新的，因为它将新的基础科学发现带到了人类群体中，并调查了迄今为止未被研究过的与乳腺癌差异有关的途径。这项拟议的研究意义重大，因为它是翻译研究连续体的第一步，有望导致发现河马信号通路改变在AA和EA女性中的作用，以及与侵袭性乳腺癌的关联。这项翻译工作最终将有助于识别侵袭性乳腺癌的高风险女性，并发现消除乳腺癌种族差异的新方法。我们的整体方法也可以应用于更大范围内与健康差异相关的其他分子途径的研究。

DESCRIPTION (provided by applicant): Although European-American (EA) women, overall, have higher breast cancer incidence than African- American (AA) women, AA women are more likely to be diagnosed at a younger age and to have more aggressive tumors, characterized by higher grade, higher proliferative indices, and lack of expression of estrogen (ER) and progesterone receptors (PR). AA women are also more likely than EAs to have triple- negative breast cancers (TNBCs), which are negative for ER, PR and HER2. These tumors have poor prognosis because they tend to be higher grade and are not responsive to anti-estrogen or anti-HER2 therapy, thus with fewer treatment options available. The reasons for these racial disparities in breast cancer aggressiveness and age at onset are unknown. The Hippo pathway was first identified in Drosophila for its control of organ size by modulating cell growth, proliferation and apoptosis, with all the core components well conserved in mammals. Down-regulation of Hippo pathway components LATS1/2 by DNA hypermethylation has been associated with large tumor size, lymph node metastasis and ER/PR negativity. Our preliminary data also showed that dysfunction of Hippo pathway components YAP/TAZ activates the EGFR signaling and YAP/TAZ is specifically increased in triple-negative and high-grade breast tumors, the subtypes more prevalent among young AA than EA women. Based on the above evidence, we hypothesize that dysfunction of the Hippo signaling pathway leads to aberrant activation of EGFR signaling in the more aggressive breast cancer, which occurs more frequently in AA than EA women. We will investigate this hypothesis in the context of two existing study populations, with the following two specific aims: 1) Determine whether YAP/TAZ-activated EGFR signaling pathway contributes to TNBC tumorigenesis, and 2) Investigate differential EGFR activation by YAP/TAZ between AA and EA women using breast cancer tumor collections. The approach is innovative, because it takes new basic science discoveries to human populations and investigates heretofore unexamined pathways in relation to breast cancer disparities. The proposed research is significant, because it is the first step in a translational continuum of research that is expected to lead to discovery of the role of the Hippo signaling pathway alterations in AA and EA women, as well as associations with aggressive breast cancer. This translational work will ultimately help identify women at a high risk of aggressive breast cancers and discover novel approaches to eliminate breast cancer racial disparities. Our integral approach may also be applied to studying other molecular pathways relevant to health disparities on a broader scale.