Abstract
Purpose
Growth factor receptor-bound 2 (Grb2)-mediated HER2 signaling is thought to play a critical role in gastric cancer development, progression and metastasis. However, little is known about their expression in gastric cancer. In this study, we try to explore their relationship with clinicopathological parameters and prognostic significance in gastric cancer patients.
Materials and methods
We examined the expression of Grb2 and HER2 in normal gastric mucosa, primary gastric cancers, and lymph node metastases using immunohistochemical analysis of tissue microarrays containing specimens obtained from 1,143 patients with gastric cancer.
Results
Grb2 was overexpressed in 48% (553/1,143) of primary tumors and 59% (155/262) of lymph node metastases. We observed significant differences in Grb2 expression between the primary tumors and the lymph node metastases (P < 0.01). Also, HER2 was overexpressed in 28% (321/1,143) of the primary tumors and 30% (79/262) of the lymph node metastases. Overexpression of Grb2 and Her2 was associated with age (>60 years), tumor location (cardia of stomach), adenocarcinoma, and high/moderate differentiation. A significant relationship was found between Grb2 and HER2 expression using Chi-Square Tests and Spearman Correlation. Overexpression of Grb2 correlated significantly with poor survival rates in both univariate and multivariate analysis.
Conclusions
Our data demonstrated a progressive amplification of Grb2 and HER2 expression in gastric carcinogenesis, suggesting the importance of Grb2 and HER2 as positive biomarkers for gastric cancer development and progression.
Similar content being viewed by others
Abbreviations
- Grb2:
-
Growth factor receptor-bound 2
- CI:
-
Confidence interval
- LN:
-
Lymph node
References
Bianco R, Melisi D, Ciardiello F et al (2006) Key cancer cell signal transduction pathways as therapeutic targets. Eur J Cancer 42:290–294. doi:10.1016/j.ejca.2005.07.034
Blok P, Craanen ME, Dekker W et al (1998) No evidence for c-erbB-2 overexpression in gastric carcinogenesis. Histopathology 32:335–339. doi:10.1046/j.1365-2559.1998.00376.x
Bose S, Chandran S, Mirocha JM et al (2006) The Akt pathway in human breast cancer: a tissue-array-based analysis. Mod Pathol 19:238–245. doi:10.1038/modpathol.3800525
Cantley LC, Auger KR, Carpenter C et al (1991) Oncogenes and signal transduction. Cell 64:281–302. doi:10.1016/0092-8674(91)90639-G
Chardin P, Cussac D, Maignan S et al (1995) The Grb2 adaptor. FEBS Lett 369:47–51. doi:10.1016/0014-5793(95)00578-W
Cheng AM, Saxton TM, Sakai R et al (1998) Mammalian Grb2 regulates multiple steps in embryonic development and malignant transformation. Cell 95:793–803. doi:10.1016/S0092-8674(00)81702-X
D’Ambrosio C, Hongo A, Li S et al (1996) The role of Grb2 in the growth and transformation of mouse embryo cells. Oncogene 12:371–378
Dharmawardana PG, Peruzzi B, Giubellino A et al (2006) Molecular targeting of growth factor receptor-bound 2 (Grb2) as an anti-cancer strategy. Anticancer Drugs 17:13–20. doi:10.1097/01.cad.0000185180.72604.ac
Downward J (1994) The GRB2/Sem-5 adaptor protein. FEBS Lett 338:113–117. doi:10.1016/0014-5793(94)80346-3
Ghaderi A, Vasei M, Maleck-Hosseini SA et al (2002) The expression of c-erbB-1 and c-erbB-2 in Iranian patients with gastric carcinoma. Pathol Oncol Res 8:252–256
Half E, Broaddus R, Danenberg KD et al (2004) HER-2 receptor expression, localization, and activation in colorectal cancer cell lines and human tumors. Int J Cancer 108:540–548. doi:10.1002/ijc.11599
Ischenko I, Petrenko O, Gu H et al (2003) Scaffolding protein Gab2 mediates fibroblast transformation by the SEA tyrosine kinase. Oncogene 22:6311–6318. doi:10.1038/sj.onc.1206742
Janes PW, Daly RJ, deFazio A et al (1994) Activation of the Ras signalling pathway in human breast cancer cells overexpressing erbB-2. Oncogene 9:3601–3608
Kaptain S, Tan LK, Chen B (2001) Her-2/neu and breast cancer. Diagn Mol Pathol 10:139–152. doi:10.1097/00019606-200109000-00001
Leng J, Lang J, Shen K et al (1997) Overexpression of p53, EGFR, c-erbB2 and c-erbB3 in endometrioid carcinoma of the ovary. Chin Med Sci J 12:67–70
Lowenstein EJ, Daly RJ, Batzer AG et al (1992) The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell 70:431–442. doi:10.1016/0092-8674(92)90167-B
MacFarlane R, Speers C, Masoudi H et al (2008) Molecular changes in the primary breast cancer versus the relapsed/metastatic lesion from a large population-based database and tissue microarray series. J Clin Oncol 26:abstr 1000
McCulloch P, Taggart T, Ochiai A et al (1997) c-erbB2 and p53 expression are not associated with stage progression of gastric cancer in Britain or Japan. Eur J Surg Oncol 23:304–309. doi:10.1016/S0748-7983(97)90669-7
Moasser MM (2007) The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 26:6469–6487. doi:10.1038/sj.onc.1210477
Motojima K, Furui J, Kohara N et al (1994) erbB-2 Expression in well-differentiated adenocarcinoma of the stomach predicts shorter survival after curative resection. Surgery 115:349–354
Oshima CT, Lanzoni VP, Iriya K et al (2001) C-erbB-2 oncoprotein in gastric carcinoma: correlation with clinical stage and prognosis. Int J Biol Markers 16:250–254
Pinto-de-Sousa J, David L, Almeida R et al (2002) c-erb B-2 expression is associated with tumor location and venous invasion and influences survival of patients with gastric carcinoma. Int J Surg Pathol 10:247–256. doi:10.1177/106689690201000402
Potrc S, Gadiijev E, Hajdinjak T et al (2007) Clinicopathological and immunohistochemical markers after radical gastrectomy for gastric cancer. Hepatogastroenterology 54:308–314
Roder DM (2002) The epidemiology of gastric cancer. Gastric Cancer 5(Suppl 1):5–11. doi:10.1007/s10120-002-0203-6
Saucier C, Papavasiliou V, Palazzo A et al (2002) Use of signal specific receptor tyrosine kinase oncoproteins reveals that pathways downstream from Grb2 or Shc are sufficient for cell transformation and metastasis. Oncogene 21:1800–1811. doi:10.1038/sj.onc.1205261
Schlessinger J, Ullrich A (1992) Growth factor signaling by receptor tyrosine kinases. Neuron 9:383–391. doi:10.1016/0896-6273(92)90177-F
Suzuki T, Tsuda T, Haruma K et al (1995) Growth of human gastric carcinomas and expression of epidermal growth factor, transforming growth factor-alpha, epidermal growth factor receptor and p185c-erbB-2. Oncology 52:385–391
Tateishi M, Toda T, Minamisono Y et al (1992) Clinicopathological significance of c-erbB-2 protein expression in human gastric carcinoma. J Surg Oncol 49:209–212. doi:10.1002/jso.2930490402
Varis A, Wolf M, Monni O et al (2002) Targets of gene amplification and overexpression at 17q in gastric cancer. Cancer Res 62:2625–2629
Verbeek BS, Adriaansen-Slot SS, Rijksen G et al (1997) Grb2 overexpression in nuclei and cytoplasm of human breast cells: a histochemical and biochemical study of normal and neoplastic mammary tissue specimens. J Pathol 183:195–203. doi:10.1002/(SICI)1096-9896(199710)183:2<195::AID-PATH901>3.0.CO;2-Y
Vizoso FJ, Corte MD, Alvarez A et al (2004) Membranous levels of c-erbB-2 oncoprotein in gastric cancer: their relationship with clinicopathological parameters and their prognostic significance. Int J Biol Markers 19:268–274
Wiedmann MW, Caca K (2005) Molecularly targeted therapy for gastrointestinal cancer. Curr Cancer Drug Targets 5:171–193. doi:10.2174/1568009053765771
Yano T, Doi T, Ohtsu A et al (2006) Comparison of HER2 gene amplification assessed by fluorescence in situ hybridization and HER2 protein expression assessed by immunohistochemistry in gastric cancer. Oncol Rep 15:65–71
Yao ZJ, King CR, Cao T et al (1999) Potent inhibition of Grb2 SH2 domain binding by non-phosphate-containing ligands. J Med Chem 42:25–35. doi:10.1021/jm980388x
Yip SS, Crew AJ, Gee JM et al (2000) Up-regulation of the protein tyrosine phosphatase SHP-1 in human breast cancer and correlation with GRB2 expression. Int J Cancer 88:363–368. doi:10.1002/1097-0215(20001101)88:3<363::AID-IJC7>3.0.CO;2-4
Yokoyama H, Ikehara Y, Kodera Y et al (2006) Molecular basis for sensitivity and acquired resistance to gefitinib in HER2-overexpressing human gastric cancer cell lines derived from liver metastasis. Br J Cancer 95:1504–1513. doi:10.1038/sj.bjc.6603459
Yonemura Y, Ninomiya I, Ohoyama S, et al (1991) Expression of c-erbB-2 oncoprotein in gastric carcinoma. Immunoreactivity for c-erbB-2 protein is an independent indicator of poor short-term prognosis in patients with gastric carcinoma. Cancer 67:2914–2918. doi:10.1002/1097-0142(19910601)67:11<2914::AID-CNCR2820671134>3.0.CO;2-G
Yu GZ, Chen Y, Long YQ et al (2008) New insight into the key proteins and pathways involved in the metastasis of colorectal carcinoma. Oncol Rep 19:1191–1204
Zang XP, Siwak DR, Nguyen TX et al (2004) KGF-induced motility of breast cancer cells is dependent on Grb2 and Erk1,2. Clin Exp Metastasis 21:437–443. doi:10.1007/s10585-004-2051-8
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yu, G.Z., Chen, Y. & Wang, J.J. Overexpression of Grb2/HER2 signaling in Chinese gastric cancer: their relationship with clinicopathological parameters and prognostic significance. J Cancer Res Clin Oncol 135, 1331–1339 (2009). https://doi.org/10.1007/s00432-009-0574-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-009-0574-8