DACH1/Eya Cell fate determination factor and mammary tumorigenesis

DACH1/Eya 细胞命运决定因子与乳腺肿瘤发生

• 批准号: 8697542
• 负责人: RICHARD G PESTELL
• 金额: $ 34.88万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697542
• 关键词: 3-Dimensional; Acetylation; Antibodies; Binding; Binding Proteins; Binding Sites; Biological Assay; Breast Cancer Cell; Breast Cancer Genetics; Breast Cancer Treatment; Breast Epithelial Cells; Cancer Etiology; Cancer cell line; Cell Communication; Cell Proliferation; Cell division; Cells; Cessation of life; DNA Binding; DNA biosynthesis; Drosophila genus; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Event; Excision; FOXO1A gene; Gene Expression; Genes; Genetic; Growth; Growth Factor Receptors; Homologous Gene; Human; Immune; Individual; Knock-out; LoxP-flanked allele; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mediating; Mesenchymal; Modeling; Molecular Genetics; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Oncogenes; Pathway interactions; Perinatal; Phenotype; Phosphorylation; Protein p53; Proteins; Proteomics; Receptor Signaling; Reporter; Resistance; Resolution; Retinal; Role; Signal Transduction; Sister; Site; Stem cells; System; Tamoxifen; Tomatoes; Transgenic Mice; Transgenic Organisms; Tumor Expansion; Tumor Stem Cells; Tumor Suppression; United States; Woman; base; blocking factor; breast tumorigenesis; cancer stem cell; cell growth; daughter cell; genetic analysis; in vivo; inhibitor/antagonist; innovation; malignant breast neoplasm; matrigel; neoplastic cell; novel; novel strategies; overexpression; public health relevance; recombinase; research study; small molecule; tumor; tumor growth; tumorigenesis

ABSTRACT These studies aim to define at a higher level of resolution the mechanism by whch the Retinal Determination Gene Network or pathway (RDGN) governs breast cancer onset and progression. Hyperactive growth factor receptor signaling remains active in many tumors that resist current therapies. The Drosophila dac gene was cloned as a dominant inhibitor of the hyperactive EGFR (Elipse). DACH1 reversed the transformed phenotype of mammary epithelial cells in 3-dimensional culture, inhibited oncogene-mediated breast tumorigenesis, blocked breast cancer epithelial cell DNA synthesis, colony formation, growth in matrigel, inhibited epithelial mesenchymal transition (EMT), tumor growth and metastasis in mice. Genetic deletion of Dach1 in the mouse results in perinatal lethality therefore we developed conditional Dach1 knockout tri- transgenic systems. Our studies provide support for a model in which DACH1 physical interactions with specific proteins coordinate DACH1-tumor suppression. These interactions govern growth suppression in breast tumor genetic subtype specific manner. DACH1 binds p53 to enhance p53 tumor suppressor functions. DACH1 binds and inhibits the function of growth inducing proteins through distinct mechanisms (YB-1, EYA1, FKHR) (Fig. 1). These studies will further characterize a novel tumor and metastasis suppressor pathway. We hypothesize that inactivation of the DACH1/EYA pathway is a key signaling event contributing to mammary tumorigenesis and metastasis. We will determine the mechanism by which DACH1 inhibits breast tumor cellular proliferation and metastasis in vivo. Photo-uncaging to induce single cell level Cre excision will allow determination of sister cell interactions and the in vivo significance of a new model of tumor suppression. Functional analyses of DACH1-secreted factors and synthetic lethal screens will identify new cancer targets.

摘要 这些研究的目的是在更高的分辨率水平上定义视网膜病变的机制。 决定基因网络或途径（RDGN）控制乳腺癌的发生和发展。极度活跃 生长因子受体信号传导在许多抵抗当前疗法的肿瘤中仍然活跃。果蝇 克隆了EGFR基因作为过度活跃的EGFR（Elipse）的显性抑制剂。DACH 1逆转了 三维培养中乳腺上皮细胞的转化表型，抑制癌基因介导的 乳腺肿瘤发生，阻断乳腺癌上皮细胞DNA合成，集落形成，在基质胶中生长， 抑制小鼠上皮间质转化（EMT）、肿瘤生长和转移。的遗传缺失 小鼠中的Dach 1会导致围产期死亡，因此我们开发了条件性Dach 1敲除三- 转基因系统我们的研究为DACH 1与DACH 2的物理相互作用模型提供了支持。 特异性蛋白协调DACH 1-肿瘤抑制。这些相互作用控制着生长抑制， 乳腺肿瘤遗传亚型特异性的方式。DACH 1结合p53以增强p53肿瘤抑制功能。 DACH 1通过不同的机制结合并抑制生长诱导蛋白的功能（YB-1，EYA 1， FKHR）（图1）。 这些研究将进一步表征一种新的肿瘤和转移抑制途径。我们假设 DACH 1/EYA通路的失活是导致乳腺肿瘤发生的关键信号事件 和转移。我们将确定DACH 1抑制乳腺肿瘤细胞增殖的机制 和体内转移。光撑开诱导单细胞水平的Cre切除将允许确定姐妹突变。 细胞相互作用和肿瘤抑制新模型的体内意义。的功能分析 DACH 1分泌因子和合成致死筛选将识别新的癌症靶点。