DACH1/Eya Cell fate determination factor and mammary tumorigenesis

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 决定基因网络或途径(RDGN)控制乳腺癌的发生和发展。过度活跃 在许多抵抗当前治疗的肿瘤中，生长因子受体信号仍然活跃。果蝇 DAC基因被克隆为高活性EGFR(Elipse)的显性抑制基因。DACH1逆转了 抑制癌基因介导的乳腺上皮细胞三维培养转化表型 乳腺肿瘤发生，阻止乳腺癌上皮细胞DNA合成，克隆形成，基质生长， 抑制小鼠上皮间充质转化(EMT)、肿瘤生长和转移。遗传性缺失 Dach1在小鼠体内可导致围产期死亡，因此我们建立了条件性Dach1基因敲除三联反应模型。 转基因系统。我们的研究支持一个模型，在该模型中，DACH1与 特定的蛋白质协调DACH1-肿瘤抑制。这些相互作用控制着经济增长抑制 乳腺肿瘤基因亚型特异性方式。DACH1结合P53以增强P53的肿瘤抑制功能。 DACH1通过不同的机制结合和抑制生长诱导蛋白的功能(YB-1，EYA1， 图1)。 这些研究将进一步描述一种新的肿瘤和转移抑制途径。我们假设 DACH1/EYA通路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DACH1抑制乳腺肿瘤细胞增殖的机制 和体内转移。光标记诱导单细胞水平的Cre切除将允许确定姊妹 细胞相互作用和肿瘤抑制新模型的体内意义。的功能分析 DACH1分泌因子和合成致死筛选将识别新的癌症靶点。

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.