The Role of Syndecan-1 in Mouse Mammary Neoplasia

Syndecan-1 在小鼠乳腺肿瘤中的作用

• 批准号: 6435180
• 负责人: CAROLINE M ALEXANDER
• 金额: $ 29.14万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-21 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6435180
• 关键词: biological signal transduction; breast neoplasms; cadherins; disease /disorder model; genetic susceptibility; genetically modified animals; laboratory mouse; ligands; mammary epithelium; mouse mammary tumor virus; neoplasm /cancer genetics; oncogenes; syndecan; tissue /cell culture; virus related neoplasm /cancer

By using mouse models, the molecules that affect the development of mammary tumors can be identified and manipulated. Various stages in the pathway to neoplasia can be characterized, including the initial growth dysregulation that serves as a precursor for tumor cells in both mouse and man. Heparan sulfate proteoglycans bind many extracellular molecules, and affect the function of at least some of them, including FGF. The cell surface heparan sulfate proteoglycan syndecan-1 (Sdc1) has been shown to collaborate with the oncogene Wnt-1 to induce hyperplasia and subsequently tumors in mouse mammary glands (Alexander et al, 2000. Nature Genetics 25, p329). Given the widespread dysregulation of Writ signaling pathways implicated in human carcinomas of many different origins, this is an important genetic interaction to characterize at the molecular level. Therefore, we aim to determine how Sdc1 interacts with the Wnt signaling pathway, using transgenic mice and genetically manipulated primary mammary epithelial cells. Mammary glands will be reconstituted in vivo by inoculating transgenic cells into host fat pads, and the activity of the Wnt signaling pathway assessed by measuring epithelial hyperplasia. This novel method conveniently tests the interaction of multiple gene products in vivo. Thus, the growth and dysregulation of Sdc1+/+ and -/- mammary epithelial cells, expressing various Sdc1 and Wnt signaling mutants, will be assessed both in vitro and in vivo. Soluble Sdc1 promotes Wnt signaling in a Drosophila culture model, and may function as a collaborator to augment signaling from the cell surface receptor complex. We will test this hypothesis by examining the epistatic interaction of Sdc1 with the primary Wnt signaling transducer, beta-catenin, and by testing for a direct interaction of Sdc1 with Wnt ligands. Sdc1- /- mice will be infected with mouse mammary tumor virus (MMTV), a mutagen that can be used to identify oncogenic loci, in order to evaluate the relative oncogenicity of specific loci and to broaden the test of tumor susceptibility in this background. In summary, this proposal aims to establish the molecular mechanism underlying the collaboration between Sdc1 and the Wnt signaling pathway that has been demonstrated in mice and may be important to man.

通过使用小鼠模型，可以识别和操纵影响乳腺肿瘤发展的分子。肿瘤形成途径中的各个阶段可以被表征，包括在小鼠和人中作为肿瘤细胞前体的初始生长失调。硫酸乙酰肝素蛋白聚糖结合许多细胞外分子，并影响其中至少一些分子的功能，包括FGF。 细胞表面硫酸乙酰肝素蛋白聚糖多配体蛋白聚糖-I（Sdc 1）已显示与致癌基因Wnt-1协作以诱导小鼠乳腺中的增生和随后的肿瘤（亚历山大等人，2000. Nature Genetics 25，p329）。 鉴于Writ信号通路的广泛失调涉及许多不同来源的人类癌症，这是一个重要的遗传相互作用，在分子水平上表征。因此，我们的目标是确定如何Sdc 1与Wnt信号通路相互作用，使用转基因小鼠和遗传操作的原代乳腺上皮细胞。 乳腺将通过将转基因细胞植入宿主脂肪垫中在体内重建，并通过测量上皮增生来评估Wnt信号传导途径的活性。 这种新的方法方便地测试多个基因产物在体内的相互作用。 因此，将在体外和体内评估表达各种Sdc 1和Wnt信号转导突变体的Sdc 1 +/+和-/-乳腺上皮细胞的生长和失调。可溶性Sdc 1在果蝇培养模型中促进Wnt信号传导，并可能作为合作者增强细胞表面受体复合物的信号传导。 我们将通过研究Sdc 1与主要Wnt信号转导蛋白β-连环蛋白的上位相互作用，以及Sdc 1与Wnt配体的直接相互作用来验证这一假设。 Sdc 1- /-小鼠将感染小鼠乳腺肿瘤病毒（MMTV）（一种可用于识别致癌基因位点的诱变剂），以评价特定基因位点的相对致癌性，并拓宽该背景下的肿瘤易感性试验。 总之，本提案旨在建立Sdc 1和Wnt信号通路之间合作的分子机制，该机制已在小鼠中得到证实，可能对人类很重要。