Loss of Par3 promotes breast cancer metastasis by compromising cell-cell cohesion.
Loss of Par3 promotes breast cancer metastasis by compromising cell-cell cohesion.
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DOI：
10.1038/ncb2663
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发表时间：
2013-02
影响因子：
21.3
通讯作者：
Muthuswamy SK
中科院分区：
文献类型：
--
作者：
Xue B;Krishnamurthy K;Allred DC;Muthuswamy SK
肿瘤细胞转移的机制以及细胞极性蛋白在这一过程中所起的作用还不是很清楚。我们报道，分割缺陷蛋白3(Par3)在人类乳腺癌的转移中调节失调，并与较高的肿瘤分级和ErbB2阳性状态有关。在体内，Par3下调与ErbB2协同诱导细胞侵袭和转移。有趣的是，转移行为与明显的间充质表型无关。然而，Par3的缺失以Tiam1/Rac-GTP途径依赖的方式抑制了E-钙粘素连接的稳定性，扰乱了细胞-细胞连接处的膜和肌动蛋白动力学，降低了细胞-细胞的凝聚力。抑制这一途径恢复了E-钙粘蛋白连接的稳定性，并阻断了缺乏Par3的细胞的侵袭行为，这表明Par3的缺失通过降低细胞-细胞凝聚力促进了ErbB2诱导的肿瘤上皮细胞的转移行为。
The mechanisms by which tumour cells metastasize and the role cell polarity proteins play in this process are not well understood. We report that Partitioning defective protein 3 (Par3) is dysregulated in metastasis in human breast cancer, and is associated with higher tumour grade and ErbB2-positive status. Downregulation of Par3 cooperated with ErbB2 to induce cell invasion and metastasis in vivo. Interestingly, the metastatic behaviour was not associated with an overt mesenchymal phenotype. However, loss of Par3 inhibited E-cadherin junction stability, disrupted membrane and actin dynamics at cell-cell junctions and decreased cell-cell cohesion in a Tiam1/Rac-GTP pathway dependent manner. Inhibition of this pathway restored E-cadherin junction stability and blocked invasive behaviour of cells lacking Par3 suggesting that loss of Par3 promotes metastatic behaviour of ErbB2-induced tumour epithelial cells by decreasing cell-cell cohesion.