Hippo signaling pathway in breast cancer disparities: a translational approach

乳腺癌差异中的 Hippo 信号通路：一种转化方法

• 批准号: 8893917
• 负责人: Jianmin Zhang
• 金额: $ 22.9万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8893917
• 关键词: African American; Age; American; Amphiregulin; Apoptosis; Archives; Basic Science; Binding Sites; Biochemistry; Biological; Breast Cancer Patient; Cancer Biology; Cell Proliferation; ChIP-seq; Collection; Contact Inhibition; DNA; Data; Diagnosis; Down-Regulation; Drosophila genus; ERBB2 gene; Epidermal Growth Factor Receptor; Estrogen Antagonists; Estrogens; European; Functional disorder; Genetic Polymorphism; Health; Human; Hypermethylation; Immunohistochemistry; Incidence; LATS1 gene; Lead; Ligands; Malignant Neoplasms; Mammals; Mammary Neoplasms; Molecular; Molecular Biology; Molecular Epidemiology; Neoplasm Metastasis; Oncogenic; Organ Size; Pathway interactions; Population; Population Study; Prevention; Progesterone Receptors; Property; Proteins; Public Health; Race; Receptor Activation; Receptor Signaling; Research; Role; Serum; Signal Pathway; Socioeconomic Status; Staining method; Stains; Structure; Translating; Tumor Subtype; Tumor Tissue; Woman; Work; base; biobank; breast tumorigenesis; cancer health disparity; cancer risk; cancer stem cell; cell growth; cell motility; epithelial to mesenchymal transition; genome-wide; health disparity; high risk; indexing; innovation; lymph nodes; mRNA Expression; malignant breast neoplasm; novel strategies; outcome forecast; overexpression; patient population; protein expression; racial disparity; screening; transcriptome sequencing; translational approach; triple-negative invasive breast carcinoma; tumor; tumorigenesis

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.

描述（由申请人提供）：尽管总体而言，欧洲-美国（EA）女性的乳腺癌发病率高于非洲-美国（AA）女性，但AA女性更有可能在更年轻时被诊断出患有更具侵袭性的肿瘤，其特征在于更高的级别、更高的增殖指数以及缺乏雌激素（ER）和孕激素受体（PR）的表达。AA女性也比EA更有可能患三阴性乳腺癌（TNBC），即ER、PR和HER 2阴性。这些肿瘤的预后较差，因为它们往往是较高级别的，并且对抗雌激素或抗HER 2治疗无反应，因此可用的治疗选择较少。乳腺癌侵袭性和发病年龄的种族差异的原因尚不清楚。Hippo通路首先在果蝇中被鉴定为通过调节细胞生长、增殖和凋亡来控制器官大小，其中所有核心组分在哺乳动物中都很保守。Hippo通路组分LATS 1/2通过DNA超甲基化的下调与大肿瘤大小、淋巴结转移和ER/PR阴性相关。我们的初步数据还显示，Hippo通路组分雅普/TAZ的功能障碍激活EGFR信号传导，并且雅普/TAZ在三阴性和高级别乳腺肿瘤中特异性增加，这些亚型在年轻AA女性中比EA女性更普遍。基于上述证据，我们假设Hippo信号通路的功能障碍导致更侵袭性乳腺癌中EGFR信号的异常激活，这在AA女性中比EA女性更常见。我们将在两个现有研究人群的背景下研究这一假设，具有以下两个特定目的：1）确定雅普/TAZ激活的EGFR信号通路是否有助于TNBC肿瘤发生，以及2）使用乳腺癌肿瘤收集物研究AA和EA女性之间由雅普/TAZ引起的差异EGFR激活。这种方法是创新的，因为它将新的基础科学发现应用于人类，并研究了迄今为止与乳腺癌差异有关的未经审查的途径。这项拟议的研究意义重大，因为它是翻译连续研究的第一步，预计将导致发现Hippo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。这项转化工作最终将有助于识别侵袭性乳腺癌高风险女性，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研究其他分子途径相关的健康差距在更广泛的范围内。