CHARACTERIZATION OF APC FUNCTION IN THE MAMMARY GLAND

乳腺 APC 功能的特征

• 批准号: 6453538
• 负责人: KATHLEEN H GOSS
• 金额: $ 3.08万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-28 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6453538
• 关键词: adenomatous polyps; breast neoplasms; cadherins; chemical carcinogen; chemical carcinogenesis; colon polyp; gene mutation; genetically modified animals; laboratory mouse; mouse mammary tumor virus; neoplasm /cancer genetics; nucleic acid repetitive sequence; tumor suppressor genes

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.

APC肿瘤抑制基因的改变是人类结直肠肿瘤发展的早期遗传变化。有趣的是，除了肠道息肉病外，携带APC突变（APCMIN）的小鼠还倾向于乳腺肿瘤。 APC的一个功能是促进β-catenin的降解并下调Wnt信号通路和靶基因转录。 我们建议APC在乳腺上皮的生长控制中起重要作用，并且该作用取决于APC调节β-catenin和Wnt信号传导的能力。 为了检验这一假设，我们将使用APCMIN小鼠来确定APC突变，β-catenin核积累与靶基因转录之间是否存在体内关联。 此外，我们将确定Wnt信号通路的破坏是否是APCMIN小鼠中乳腺肿瘤发生的必要条件。 将通过下调β-catenin的调节或通过中断TCF-介导转录来产生转基因小鼠在乳腺中抑制Wnt信号传导。 这些转基因抑制APCMIN小鼠中肿瘤发生的能力将进行检查。 这些研究将阐明APC抑制乳腺中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非常有价值。