CHARACTERIZATION OF APC FUNCTION IN THE MAMMARY GLAND

APC抑癌基因的改变是人类结直肠癌发生发展过程中的早期基因改变。有趣的是，携带APC突变(ApcMin)的小鼠除了肠息肉病外，还容易患上乳腺肿瘤。APC的功能之一是促进β-连环蛋白的降解，下调Wnt信号通路和靶基因转录。我们认为APC在乳腺上皮细胞的生长控制中起着重要的作用，并且这一作用依赖于APC调节β-连环蛋白和Wnt信号的能力。为了验证这一假设，我们将使用ApcMin小鼠来确定APC突变、β-连环蛋白核积累和靶基因转录之间是否存在体内关联。此外，我们将确定Wnt信号通路的中断是否对ApcMin小鼠的乳腺肿瘤的发生是必要的。将产生转基因小鼠，其中Wnt信号在乳腺中通过下调β-连环蛋白或中断Tcf中介转录而被抑制。这些转基因抑制ApcMin小鼠肿瘤形成的能力将被检测。这些研究将阐明APC抑制乳腺肿瘤形成的分子机制，并将对设计乳腺癌的治疗和化学预防策略具有价值。

Alteration of the APC tumor suppressor gene is an early genetic change in the development of colorectal tumors in humans. Interestingly, mice carrying an Apc mutation (ApcMin) are predisposed to mammary neoplasia in addition to intestinal polyposis. One function of APC is to facilitate the degradation of beta-catenin and down-regulate the Wnt signaling pathway and target gene transcription. We propose that APC plays an important role in growth control of the mammary epithelium, and that this role is dependent on the ability of APC to regulate beta-catenin and Wnt signaling. To test this hypothesis, we will use ApcMin mice to determine if there is an in vivo association between Apc mutation, beta-catenin nuclear accumulation and target gene transcription. Furthermore, we will determine if disruption of the Wnt signaling pathway is necessary for mammary tumorigenesis in ApcMin mice. Transgenic mice will be generated in which Wnt signaling is inhibited in the mammary gland by down- regulation of beta-catenin or by interruption of Tcf-mediate transcription. The ability of these transgenes to suppress tumorigenesis in ApcMin mice will be examined. These studies will elucidate the molecular mechanism by which APC suppresses tumorigenesis in the mammary gland and will be valuable in designing therapeutic and chemopreventive strategies for breast cancer.