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Persistent transactivation of EGFR and ErbB2/HER2 by protease-activated receptor-1 promotes breast carcinoma cell invasion

Oncogene volume 27, pages 4434–4445 (2008)Cite this article

Abstract

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 Gαi/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.

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Acknowledgements

We thank Dr Pilar Blancafort, Dr Lee Graves and Dr Shelton Earp III for advice and generously providing reagents. This study was supported by NIH grant HL073328, Susan G Komen Breast Cancer Foundation Award and an American Heart Association-established Investigator Award (to JT) and NIH grants GM30324 and DK37871 (to GLJ).

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Authors and Affiliations

  1. Department of Pharmacology, Lineberger Comprehensive Cancer Center, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    P Arora, B D Cuevas, A Russo, G L Johnson & J Trejo

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  1. P Arora
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  2. B D Cuevas
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  3. A Russo
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  4. G L Johnson
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  5. J Trejo
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Correspondence to J Trejo.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Arora, P., Cuevas, B., Russo, A. et al. Persistent transactivation of EGFR and ErbB2/HER2 by protease-activated receptor-1 promotes breast carcinoma cell invasion. Oncogene 27, 4434–4445 (2008). https://doi.org/10.1038/onc.2008.84

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