DACH1/Eya Cell fate determination factor and mammary tumorigenesis

描述（由申请人提供）：这些研究旨在以更高的分辨率定义视网膜决定基因网络或途径（RDGN）控制乳腺癌发生和进展的机制。过度活跃的生长因子受体信号在许多抵抗当前治疗的肿瘤中仍然活跃。果蝇dac基因被克隆为过度活跃的EGFR （ellipse）的显性抑制剂。DACH1在三维培养中逆转乳腺上皮细胞转化表型，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、基质生长，抑制小鼠上皮间充质转化（EMT）、肿瘤生长和转移。小鼠Dach1基因缺失会导致围产期死亡，因此我们开发了条件Dach1基因敲除三转基因系统。我们的研究为DACH1与特定蛋白的物理相互作用协调DACH1肿瘤抑制的模型提供了支持。这些相互作用以特定的方式控制着乳腺肿瘤基因亚型的生长抑制。DACH1结合p53增强p53的抑瘤功能。DACH1通过不同的机制（YB-1、EYA1、FKHR）结合并抑制生长诱导蛋白的功能（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DACH1/EYA通路失活是促进乳腺肿瘤发生和转移的关键信号事件。我们将在体内确定DACH1抑制乳腺肿瘤细胞增殖和转移的机制。光剥离诱导单细胞水平的Cre切除将允许确定姐妹细胞相互作用和肿瘤抑制新模型的体内意义。dach1分泌因子的功能分析和合成致死筛选将确定新的癌症靶点。

DESCRIPTION (provided by applicant): These studies aim to define at a higher level of resolution the mechanism by which 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.