Expression and signaling activity of Wnt-5a/discoidin domain receptor-1 and Syk plays distinct but decisive roles in breast cancer patient survival.
Expression and signaling activity of Wnt-5a/discoidin domain receptor-1 and Syk plays distinct but decisive roles in breast cancer patient survival.
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发表时间：
2005-01
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通讯作者：
J. Dejmek;K. Leandersson;J. Manjer;A. Bjartell;S. Emdin;W. Vogel;G. Landberg;T. Andersson
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作者：
J. Dejmek;K. Leandersson;J. Manjer;A. Bjartell;S. Emdin;W. Vogel;G. Landberg;T. Andersson
在不同的研究中，Wnt-5a（一种G蛋白偶联受体配体）或Syk（一种细胞内激酶）的缺失与乳腺癌患者预后不良有关。这两种蛋白质都参与细胞粘附，这是上皮癌转移的关键事件。在这里，我们研究了Syk是否是Wnt-5a/盘状结构域受体-1（DDR 1）信号通路的一部分，以及这些蛋白质的信号相互作用是否对乳腺癌特异性生存很重要。实验设计在乳腺细胞系中解决Wnt-5a/DDR 1和Syk之间的信号传导相互作用。在94例原发性乳腺癌中检测其mRNA和蛋白水平及其临床相关性。结果Wnt-5a和Syk在5种肿瘤细胞系中的表达存在相关性。然而，尽管Syk和Wnt-5a依赖性粘附受体DDR 1之间存在组成性关联，但我们没有发现Wnt-5a/DDR 1介导的Syk激活的证据。相反，β（1）整合素启动粘附诱导的Syk活化。在乳腺癌患者的肿瘤中，Wnt-5a和Syk的蛋白表达分别在翻译和转录水平上受到不同的调控。乳腺癌特异性生存分析显示，原发性肿瘤中Wnt-5a和Syk的存在对有利的结局具有良好的预测价值。有趣的是，两种蛋白质的同时缺失并不比任何一种蛋白质的缺失更能降低存活率。结论：尽管Wnt-5a和Syk蛋白表达的调节存在差异，且缺乏信号相互作用，但我们的临床数据表明，乳腺癌的良好预后需要两者的表达和信号活性。
PURPOSE The loss of Wnt-5a, a G-protein-coupled receptor ligand, or Syk, an intracellular kinase, has in separate studies been associated with poor prognosis of breast cancer patients. Both proteins are involved in cell adhesion, a key event in epithelial cancer metastasis. Here, we have investigated whether Syk is part of the Wnt-5a/discoidin domain receptor-1 (DDR1) signaling pathway and if a signaling interaction of these proteins is important for breast cancer-specific survival. EXPERIMENTAL DESIGN The signaling interactions between Wnt-5a/DDR1 and Syk were addressed in mammary cell lines. Their mRNA and protein levels and the respective clinical correlates were investigated in 94 cases of primary breast cancer. RESULTS The expression of Wnt-5a and Syk correlated in four of five tumor cell lines. However, despite a constitutive association between Syk and the Wnt-5a-dependent adhesion receptor DDR1, we found no evidence of a Wnt-5a/DDR1-mediated activation of Syk. Instead, beta(1) integrins initiate the adhesion-induced activation of Syk. In tumors from breast cancer patients, the protein expression of Wnt-5a and Syk were differently regulated at the translational and transcriptional level, respectively. Analysis of breast cancer-specific survival revealed that the presence of Wnt-5a and Syk in primary tumors has good predictive value for a favorable outcome. Intriguingly, a simultaneous loss of both proteins did not reduce survival more than loss of either. CONCLUSIONS Despite the difference in regulation of Wnt-5a and Syk protein expression and their lack of signaling interaction, our clinical data indicate that a favorable prognosis in breast cancer requires the expression and signaling activity of both.