CHARACTERIZATION OF APC FUNCTION IN THE MAMMARY GLAND

APC肿瘤抑制基因的改变是人类结直肠肿瘤发展中的早期遗传变化。有趣的是，携带Apc突变（ApcMin）的小鼠除了肠息肉病外，还易患乳腺肿瘤。 APC的功能之一是促进β-catenin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，并且这种作用依赖于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，我们将确定是否Wnt信号通路的中断是必要的乳腺肿瘤发生在ApcMin小鼠。 将产生转基因小鼠，其中通过下调β-连环蛋白或通过中断Tcf介导的转录来抑制乳腺中的Wnt信号传导。 将检查这些转基因抑制ApcMin小鼠中肿瘤发生的能力。 这些研究将阐明APC抑制乳腺肿瘤发生的分子机制，并将在设计乳腺癌的治疗和化学预防策略方面具有价值。

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.