To the Editor,
The recent article by Shi et al. provided for highly stimulating reading [Citation1]. Grb2 may play a major role in tumor progression in a number of other systemic malignancies.
Grb2 plays a prominent role in tumor progression in mammary malignancies. Typically, up-regulated Grb2 levels are seen in breast cancers [Citation2]. It plays a major role in proliferation of breast cancer cells especially those that overexpress ErbB2. It mediates its modulatory role by accentuating Ets-2-dependent transcription within the breast cancer cells [Citation3]. In addition, it also increases activation of the Akt signaling pathway. Besides this, it may also up-regulate the activity of the protein tyrosine phosphatase SHP-1 [Citation4]. Augmentation of the intra-tumoral levels of “Grb2 and the hSos-1 Ras GDP-GTP” complexes is typically seen following up-regulation of Grb2 levels [Citation5]. Grb2 along with Shc also has an activating impact on extracellular signal-regulated kinases within the breast tumor [Citation6]. These changes have been confirmed recently in MCF-7 breast cancer cell lines [Citation7].
Similar up-regulation of Grb2 has been noted in pulmonary malignancies. For instance, only 12% of benign lung tissue stains positive for Grb2 in contrast to nearly 62% of all squamous cell lung carcinomas [Citation8]. Interestingly, the PSGF signal to Grb2 is mediated by Lad and results in accentuated AP-1 activation within the tumor cells [Citation9]. Similar accentuation of Grb2 expression is seen in gastrointestinal malignancies such as gastric carcinomas. For instance, up-regulated Grb2 levels are seen in nearly 48% of all gastric malignancies [Citation10]. Malignant gastric tumors in the gastric cardia tend to express higher levels of Grb2. Also higher levels have been noted in gastric carcinoma patients over the age of 60 years. Not surprisingly, decreased overall survival is seen in patients with up-regulated Grb2 expression.
The above examples clearly illustrate the significant role of Grb2 in tumor progression in a number of systemic malignancies and the need for further large scale studies to fully explore and understand its role in tumor evolution and growth.
Declaration of interest: The author report no conflicts of interest. The author alone is responsible for the content and writing of the paper.
References
- Shi L, Sun X, Zhang J, Zhao C, Li H, Liu Z, et al. Gab2 expression in glioma and its implications for tumor invasion. Acta Oncol Epub 2013;52:1739–50.
- Daly RJ, Binder MD, Sutherland RL. Overexpression of the Grb2 gene in human breast cancer cell lines. Oncogene 1994;9:2723–7.
- Mendoza-Gamboa E, Siwak DR, Tari AM. The HER2/Grb2/Akt pathway regulates the DNA binding activity of AP-1 in breast cancer cells. Oncol Rep 2004;12:903–8.
- Dankort D, Maslikowski B, Warner N. Grb2 and Shc adapter proteins play distinct roles in Neu (ErbB-2)-induced mammary tumorigenesis: Implications for human breast cancer. Mol Cell Biol 2001;21:1540–51.
- Lim SJ, Lopez-Berestein G, Hung MC, Lupu R, Tari AM. Grb2 downregulation leads to Akt inactivation in heregulin-stimulated and ErbB2-overexpressing breast cancer cells. Oncogene 2000;19:6271–6.
- Yip SS, Crew AJ, Gee JM. Up-regulation of the protein tyrosine phosphatase SHP-1 in human breast cancer and correlation with GRB2 expression. Int J Cancer 2000; 88:363–8.
- Zang XP, Siwak DR, Nguyen TX, Tari AM, Pento JT. KGF-induced motility of breast cancer cells is dependent on Grb2 and Erk1,2. Clin Exp Metastasis 2004;21: 437–43.
- Xu XL, Wang X, Chen ZL. Overexpression of Grb2- associated binder 2 in human lung cancer. Int J Biol Sci 2011;7:496–504.
- Park D, Choi YB, Han MK, Kim UH, Shin J, Yun Y. Adaptor protein Lad relays PDGF signal to Grb2 in lung cells: A tissue-specific PDGF signal transduction. Biochem Biophys Res Commun 2001;284:275–81.
- Yu GZ, Chen Y, Wang JJ. Overexpression of Grb2/ HER2 signaling in Chinese gastric cancer: Their relationship with clinicopathological parameters and prognostic significance. J Cancer Res Clin Oncol 2009;135: 1331–9.