Persistent transactivation of EGFR and ErbB2/HER2 by protease-activated receptor-1 promotes breast carcinoma cell invasion
Persistent transactivation of EGFR and ErbB2/HER2 by protease-activated receptor-1 promotes breast carcinoma cell invasion
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DOI：
10.1038/onc.2008.84
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发表时间：
2008-07-24
期刊：
影响因子：
8
通讯作者：
Trejo, J.
中科院分区：
文献类型：
--
作者：
Arora, P.;Cuevas, B. D.;Trejo, J.
ErbB信号的过度激活与转移性乳腺癌有关。然而，导致ErbB信号失调和促进乳腺癌细胞侵袭的机制仍然知之甚少。在乳腺癌细胞侵袭过程中，导致ErbB活化的一条途径涉及g蛋白偶联受体（gpcr）的反激活。蛋白酶激活受体1 （PAR1）是一种由细胞外蛋白酶激活的GPCR，在浸润性乳腺癌中过度表达。PAR1也被认为在乳腺癌的侵袭和转移中起作用，但PAR1如何参与这些过程尚不清楚。在这项研究中，我们报告了凝血酶对PAR1的蛋白水解激活在浸润性乳腺癌中诱导了EGFR和ErbB2/HER2的持续反激活，而在正常乳腺上皮细胞中则没有。par1刺激的EGFR和ErbB2转激活导致细胞外信号调节激酶-1和-2信号传导延长，促进乳腺癌细胞侵袭。我们还发现PAR1信号通过G α (i/o)和金属蛋白酶活性对ErbB的转激活和细胞侵袭至关重要。最后，我们证明了PAR1在浸润性乳腺癌中的表达是肿瘤生长的必要条件，通过乳腺脂肪垫异种移植评估。这些研究揭示了PAR1（一种由肿瘤产生的蛋白酶激活的受体）在ErbB信号的过度激活中起关键作用，从而促进乳腺癌细胞的侵袭。
Hyperactivation of ErbB signaling is implicated in metastatic breast cancer. However, the mechanisms that cause dysregulated ErbB signaling and promote breast carcinoma cell invasion remain poorly understood. One pathway leading to ErbB activation that remains unexplored in breast carcinoma cell invasion involves transactivation by G-protein-coupled receptors (GPCRs). Protease-activated receptor-1 (PAR1), a GPCR activated by extracellular proteases, is overexpressed in invasive breast cancer. PAR1 is also proposed to function in breast cancer invasion and metastasis, but how PAR1 contributes to these processes is not known. In this study, we report that proteolytic activation of PAR1 by thrombin induces persistent transactivation of EGFR and ErbB2/HER2 in invasive breast carcinoma, but not in normal mammary epithelial cells. PAR1-stimulated EGFR and ErbB2 transactivation leads to prolonged extracellular signal-regulated kinase-1 and -2 signaling and promotes breast carcinoma cell invasion. We also show that PAR1 signaling through G alpha(i/o) and metalloprotease activity is critical for ErbB transactivation and cellular invasion. Finally, we demonstrate that PAR1 expression in invasive breast carcinoma is essential for tumor growth in vivo assessed by mammary fat pad xenografts. These studies reveal a critical role for PAR1, a receptor activated by tumor-generated proteases, in hyperactivation of ErbB signaling that promotes breast carcinoma cell invasion.