β-catenin is a downstream effector of Wnt-mediated tumorigenesis in the mammary gland
β-catenin is a downstream effector of Wnt-mediated tumorigenesis in the mammary gland
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DOI：
10.1038/sj.onc.1204586
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发表时间：
2001-08-23
期刊：
影响因子：
8
通讯作者：
Leder, P
中科院分区：
文献类型：
--
作者：
Michaelson, JS;Leder, P
Wnt信号转导通路与小鼠乳腺肿瘤发生有关。β-连环蛋白是该途径的关键下游效应物，它与转录因子Tcf/Lef家族相互作用，从而激活Tcf/Lef家族。在许多人类肿瘤中发现β-连环蛋白水平升高，特别是结肠癌。最近，β-连环蛋白水平升高与乳腺癌预后不良有关。为了评估β-连环蛋白在乳腺癌中的可能作用，我们创建了携带驱动活化形式的β-连环蛋白的MMTV-LTR的转基因小鼠。这些小鼠发生乳腺增生和乳腺腺癌，其表型与表达MMT驱动的Writ基因的转基因小鼠非常相似。事实上，Wnt介导的腺癌中乳腺肿瘤的组织病理学与我们的β-连环蛋白介导的疾病模型中观察到的相同。此外，推定的β-连环蛋白转录靶点，细胞周期蛋白D1和c-myc，在β-连环蛋白介导的乳腺肿瘤和细胞系中升高。这些观察结果支持这样的观点，即致癌Wnt途径在乳腺增生和癌的背景下通过β-连环蛋白及其靶点起作用。
The Wnt signal transduction pathway has been implicated in mammary tumorigenesis in the mouse. beta -catenin, a key downstream effector of this pathway interacts with and thus activates the Tcf/Lef family of transcription factors. Elevated levels of beta -catenin have been found in many human tumors, notably colon carcinomas. Recently, elevated levels of beta -catenin have been associated with poor prognosis in human adenocarcinoma of the breast. In order to assess the possible role of beta -catenin in mammary carcinoma, we have created transgenic mice bearing the MMTV-LTR driving an activated form of beta -catenin. These mice develop mammary gland hyperplasia and mammary adenocarcinoma, a phenotype very similar to that of transgenic mice expressing an MMTV-driven Writ gene. Indeed, the histopathology of the mammary tumors in Wnt-mediated adenocarcinoma is identical to that observed in our beta -catenin-mediated disease model. Furthermore, putative beta -catenin transcriptional targets, cyclin D1 and c-myc, are elevated in beta -catenin-mediated mammary tumors and cell lines. These observations support the notion that the oncogenic Wnt pathway operates via beta -catenin and its targets in the context of mammary hyperplasia and carcinoma.