Conditional Wwox deletion in mouse mammary gland by means of two Cre recombinase approaches.
Conditional Wwox deletion in mouse mammary gland by means of two Cre recombinase approaches.
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DOI：
10.1371/journal.pone.0036618
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Aldaz CM
中科院分区：
文献类型：
--
作者：
Ferguson BW;Gao X;Kil H;Lee J;Benavides F;Abba MC;Aldaz CM
在包括乳腺癌在内的许多不同癌症中已经报道了WWOX表达的缺失。阐明该基因在成人组织中的功能，用完整的Wwox敲除模型是不可能的。在这里，我们的特点是第一个条件模型的Wwox消融小鼠乳腺上皮细胞利用两个转基因株表达Cre重组酶，角蛋白5-Cre（BK 5-Cre）和MMTV-Cre。在BK 5-Cre模型中，我们在KO乳腺中观察到非常有效的Wwox消融。然而，BK 5-Cre Wwox KO动物由于未知原因过早死亡。在MMTV-Cre模型中，我们观察到乳腺上皮中Wwox的显著消融，对存活没有影响。在这两种模型中，我们发现Wwox缺失导致乳腺分支形态发生受损。我们证明，Wwox的损失是不是在我们的KO模型致癌。此外，未观察到增殖增加或癌前病变发展的证据。在所有模型中，单个Wwox等位基因的丢失（即单倍不足）在乳腺中均不具有任何可观察到的表型效应。为了更好地理解Wwox在乳腺中的功能，进行了转录组谱分析。我们观察到Wwox消融导致参与各种细胞过程的基因的失调。我们发现非典型Wnt配体Wnt 5a的表达在Wwox KO乳腺上皮中显著上调。有趣的是，我们还确定了Jak/Stat 3信号通路的组分在KO小鼠中上调，这与磷酸化Stat 3信号传导的非常稳健的增加相关，这需要进一步测试。尽管Wwox在乳腺癌和其他癌症中的表达缺失已经得到了很好的证明，但我们的研究结果表明，Wwox并不像以前认为的那样是一种经典的肿瘤抑制因子。
Loss of WWOX expression has been reported in many different cancers including breast cancer. Elucidating the function of this gene in adult tissues has not been possible with full Wwox knockout models. Here we characterize the first conditional models of Wwox ablation in mouse mammary epithelium utilizing two transgenic lines expressing Cre recombinase, keratin 5-Cre (BK5-Cre) and MMTV-Cre. In the BK5-Cre model we observed very efficient Wwox ablation in KO mammary glands. However, BK5-Cre Wwox KO animals die prematurely for unknown reasons. In the MMTV-Cre model we observed significant ablation of Wwox in mammary epithelium with no effect on survival. In both of these models we found that Wwox deletion resulted in impaired mammary branching morphogenesis. We demonstrate that loss of Wwox is not carcinogenic in our KO models. Furthermore, no evidence of increase proliferation or development of premalignant lesions was observed. In none of the models did loss of a single Wwox allele (i.e. haploinsufficiency) have any observable phenotypic effect in mammary gland. To better understand the function of Wwox in the mammary gland, transcriptome profiling was performed. We observed that Wwox ablation results in the deregulation of genes involved in various cellular processes. We found that expression of the non-canonical Wnt ligand, Wnt5a, was significantly upregulated in Wwox KO mammary epithelium. Interestingly, we also determined that components of the Jak/Stat3 signaling pathway were upregulated in KO mice and this correlated with a very robust increase in phospho-Stat3 signaling, which warrants further testing. Even though the loss of Wwox expression in breast and other cancers is very well documented, our findings suggest that Wwox does not act as a classical tumor suppressor as previously thought.
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