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: 8774394
• 负责人: Jianmin Zhang
• 金额: $ 19.09万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8774394
• 关键词: African American; Age; American; Amphiregulin; Apoptosis; Archives; Basic Science; Binding Sites; Biochemistry; Biological; Cancer Biology; Cancer Patient; 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; public health relevance; 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，欧美（EA）女性的乳腺癌发生率高于非裔美国人（AA）妇女，但AA妇女更有可能在年轻时被诊断出来，并且患有更侵略性的肿瘤，其特征是较高，增生性较高，缺乏雌激素（ER）和雌激素（ER）和叶酸受体（PR）（PR）。 AA妇女也比EA的乳房癌（TNBC）更有可能，这些乳腺癌对ER，PR和HER2负面。这些肿瘤的预后较差，因为它们倾向于更高级别，并且对抗雌激素或抗HER2治疗没有反应，因此可用的治疗选择较少。乳腺癌侵略性和发病年龄的这些种族差异的原因尚不清楚。河马途径首先在果蝇中通过调节细胞生长，增殖和凋亡来控制器官大小，并在哺乳动物中保守所有核心成分，以控制器官大小。通过DNA高甲基化对河马途径成分LATS1/2的下调与肿瘤大小，淋巴结转移和ER/PR否定性有关。我们的初步数据还表明，河马途径成分YAP/TAZ激活EGFR信号传导和YAP/TAZ的功能障碍在三阴性和高级乳腺肿瘤中明确增加了，年轻AA中的亚型比EA女性更普遍。根据上述证据，我们假设河马信号通路的功能障碍会导致更具侵略性的乳腺癌中EGFR信号的异常激活，而AA在AA中的发生频率比EA女性更频繁。我们将在两个现有研究人群的背景下研究这一假设，以下两个具体目的：1）确定YAP/TAZ激活的EGFR信号传导途径是否有助于TNBC肿瘤发生，并且2）研究使用乳腺癌肿瘤分组的AA和EA女性之间的YAP/TAZ差异EGFR激活。这种方法具有创新性，因为它为人类人群带来了新的基础科学发现，并研究了与乳腺癌差异有关的迄今未经检查的途径。拟议的研究很重要，因为它是翻译连续研究的第一步，预计会导致发现河马信号通路途径改变AA和EA妇女的作用，以及与侵略性乳腺癌的关联。这项翻译工作最终将有助于确定具有侵略性乳腺癌风险的女性，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与健康差异相关的其他分子途径。