A targeted constitutive mutation in the APC tumor suppressor gene underlies mammary but not intestinal tumorigenesis.
A targeted constitutive mutation in the APC tumor suppressor gene underlies mammary but not intestinal tumorigenesis.
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DOI：
10.1371/journal.pgen.1000547
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发表时间：
2009-07
期刊：
影响因子：
4.5
通讯作者：
Fodde R
中科院分区：
文献类型：
--
作者：
Gaspar C;Franken P;Molenaar L;Breukel C;van der Valk M;Smits R;Fodde R
腺瘤性结肠息肉病 (APC) 基因的种系突变导致家族性腺瘤性息肉病 (FAP)，这是一种常染色体显性遗传倾向，可导致多发性结直肠腺瘤和广泛的肠外肿瘤的发生。此外，体细胞APC突变在大多数散发性结直肠癌中发挥限速和起始作用。尽管具有多功能性质，APC 基因的主要肿瘤抑制活性在于其调节 Wnt/β-连环蛋白信号传导的能力。值得注意的是，在APC基因上，不同突变等位基因编码的截短蛋白的长度和稳定性、它们编码的Wnt/β-连环蛋白信号活性的相应水平以及肠道和肠外肿瘤的发生率和分布之间已经建立了基因型-表型相关性。在这里，我们报告了一种新的小鼠模型，Apc1572T，是通过针对内源 Apc 基因中密码子 1572 处的截短突变而获得的。与与多灶性肠肿瘤相关的其他 Apc 突变相比，这种亚等位突变等位基因导致 Wnt/β-连环蛋白信号激活处于中等水平。尽管突变具有组成性，但 Apc +/1572T 小鼠没有患肠癌的倾向，但两性都会发生多灶性乳腺癌和随后的肺转移。 Apc1572T 原发性乳腺肿瘤的组织学具有高度异质性，具有管腔、肌上皮和鳞状细胞系，让人想起人类乳腺癌的化生性癌。 Apc +/1572T 小鼠的惊人表型表明，特定剂量的 Wnt/β-catenin 信号传导活性会不同程度地影响组织稳态，并以器官特异性方式启动肿瘤发生。尽管信号转导途径通常被描述为“开关”系统，但信号转导的更定量方面可能代表了调节下游生物学结果的非常重要的手段。经典 Wnt 信号通路成员的突变是人类癌症中最常见的缺陷之一。然而，目前尚不清楚哪些因素决定了 Wnt 组成型激活时产生的肿瘤的组织和器官特异性。此前，我们在 Apc 肿瘤抑制基因上生成了一系列亚等位基因，并表明胚胎干细胞的分化潜力取决于这些突变体编码的 Wnt/β-catenin 信号传导剂量。同样，对人类和小鼠肠道肿瘤中 Apc 基因发生的两个突变命中的分析表明，选择这些突变是为了保留 β-连环蛋白下调的特定残留剂量。在这里，我们通过靶向种系 Apc 突变，与已知触发肠道肿瘤发生的其他突变体相比，编码非常低水平的 Wnt 信号激活，为这种“恰到好处”的信号传导模型提供进一步支持。尽管这种突变具有组成性，但杂合小鼠表现出显着且高度渗透的多灶性和转移性乳腺癌倾向，而没有大多数 Apc 小鼠模型的胃肠道肿瘤表型特征。
Germline mutations in the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis (FAP), an autosomal dominant hereditary predisposition to the development of multiple colorectal adenomas and of a broad spectrum of extra-intestinal tumors. Moreover, somatic APC mutations play a rate-limiting and initiating role in the majority of sporadic colorectal cancers. Notwithstanding its multifunctional nature, the main tumor suppressing activity of the APC gene resides in its ability to regulate Wnt/β-catenin signaling. Notably, genotype–phenotype correlations have been established at the APC gene between the length and stability of the truncated proteins encoded by different mutant alleles, the corresponding levels of Wnt/β-catenin signaling activity they encode for, and the incidence and distribution of intestinal and extra-intestinal tumors. Here, we report a novel mouse model, Apc1572T, obtained by targeting a truncated mutation at codon 1572 in the endogenous Apc gene. This hypomorphic mutant allele results in intermediate levels of Wnt/β-catenin signaling activation when compared with other Apc mutations associated with multifocal intestinal tumors. Notwithstanding the constitutive nature of the mutation, Apc +/1572T mice have no predisposition to intestinal cancer but develop multifocal mammary adenocarcinomas and subsequent pulmonary metastases in both genders. The histology of the Apc1572T primary mammary tumours is highly heterogeneous with luminal, myoepithelial, and squamous lineages and is reminiscent of metaplastic carcinoma of the breast in humans. The striking phenotype of Apc +/1572T mice suggests that specific dosages of Wnt/β-catenin signaling activity differentially affect tissue homeostasis and initiate tumorigenesis in an organ-specific fashion. Although signal transduction pathways are often described as “on–off” systems, the more quantitative aspects of signalling are likely to represent a very important means of regulation of the downstream biological outcomes. Mutations in members of the canonical Wnt signaling pathway represent among the most common defects in human cancers. However, it is yet unclear which factors determine tissue and organ specificity of the tumours arising upon Wnt constitutive activation. Previously, we have generated a series of hypomorphic alleles at the Apc tumor suppressor gene and showed that the differentiation potential of embryonic stem cells is dependent on the dosage of Wnt/β-catenin signalling these mutants encode for. Likewise, analysis of the two mutational hits occurring at the Apc gene in human and mouse intestinal tumors showed that these are selected to retain specific residual dosages of β-catenin downregulation. Here, we provide further support for this “just-right” signalling model by targeting a germline Apc mutation encoding for very low levels of Wnt signalling activation when compared with other mutants known to trigger intestinal tumorigenesis. Notwithstanding the constitutive nature of this mutation, heterozygous mice show a remarkable and highly penetrant predisposition to multifocal and metastatic mammary cancers without the GI tract tumor phenotype characteristic of the majority of Apc mouse models.
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影响因子：
8
作者：
Alberici, P;Jagmohan-Changur, S;Fodde, R
通讯作者：
Fodde, R
影响因子：
64.8
作者：
NUSSE, R;VANOOYEN, A;VARMUS, H
通讯作者：
VARMUS, H
Wnt途径基因的遗传变化是乳房化生癌中的常见事件。
DOI：
10.1158/1078-0432.ccr-07-4379
发表时间：
2008-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Hayes MJ;Thomas D;Emmons A;Giordano TJ;Kleer CG
通讯作者：
Kleer CG
影响因子：
3.5
作者：
Albuquerque, C;Breukel, C;Smits, R
通讯作者：
Smits, R
影响因子：
0.7
作者：
Gaspar, C;Fodde, R
通讯作者：
Fodde, R