Abstract
Background
Owing to the special importance of the HER family in tumorigenesis, the downstream signaling pathways and effectors have become the key molecules in the strategy of carcinoma-targeted therapy. Recent evidence that HER3 is responsible for tumor resistance to therapeutic agents targeting EGFR or HER2/neu, along with the new findings that HER3 is involved in the process of dedifferentiation of gastric cancer (GC) have highlighted the critical role of HER3 in cancer research. HER3 is becoming a new targeted molecule in cancer treatment. Here, we comparatively investigated the expression of HER2/neu and HER3 in gastric cancer of two pathologic types (intestinal type and diffuse type) using immunohistochemistry (IHC) and analyzed the correlation between overexpression of HER2 and HER3 and clinicopathologic parameters.
Methods
An IHC study for HER2 and HER3 was performed on 102 formalin-fixed, paraffin-embedded specimens of GC—60 intestinal and 42 diffuse types. The correlation between overexpression of HER2 and HER3 and clinicopathologic parameters was statistically analyzed.
Results
In the GC group, overexpression of HER2 and HER3 was detected in 19 (18.6%) and 14 (13.7%) of 102 GC patients, respectively. In a nontumorous group of 102 specimens, 5 were HER2-positive (4.9%) (18.6% vs. 4.9%, p < 0.01), and 2 were HER3-positive (2.0%) (13.7% vs. 2.0%, p < 0.01). No co-overexpression of HER2 and HER3 was observed. The intestinal type of GC exhibited a higher rate of HER2 overexpression than did the diffuse type (26.7% vs. 7.1%, p < 0.05), whereas the diffuse type of GC exhibited a significantly higher rate of HER3 overexpression than did the intestinal type (26.2% vs. 5.0%, p < 0.01). The overexpression rates of HER2 and HER3 in phase III–IV (TNM stage) disease were significantly higher than that in phase I–II disease (24.0% vs. 7.7%, p < 0.05 and 22.0% vs. 5.8%, p < 0.05, respectively). HER2 and HER3 overexpression was also correlated with a significantly worse survival (p = 0.046 and 0.024, respectively).
Conclusions
The selective overexpression of HER2 and HER3 in the two histologic types of gastric cancer is strongly associated with a poor prognosis. Being an important member of the HER family, HER3 may become another candidate for molecular-targeted therapy in gastric cancer, especially for the diffuse histologic type.
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References
Bulanov D (2007) Gastric cancer-current state of the problem. Part I. Epidemiology, pathology, classification, staging. Khirurgiia (Sofiia) 4:48–59
Roder DM (2002) The epidemiology of gastric cancer. Gastric Cancer 5:5–11
Ahmed KM, Cao N, Li JJ (2006) HER-2 and NF-kappaB as the targets for therapy-resistant breast cancer. Anticancer Res 26:4235–4243
Jin Q, Esteva FJ (2008) Cross-talk between the ErbB/HER family and the type I insulin-like growth factor receptor signaling pathway in breast cancer. J Mammary Gland Biol Neoplasia 13:485–498
Derin D, Eralp Y, Ozluk Y et al (2008) Lower level of MAPK expression is associated with anthracycline resistance and decreased survival in patients with hormone receptor negative breast cancer. Cancer Invest 26:671–679
Burris H, Rocha-Lima C (2008) New therapeutic directions for advanced pancreatic cancer: targeting the epidermal growth factor and vascular endothelial growth factor pathways. Oncologist 13:289–298
Duneau JP, Vegh AP, Sturgis JN (2007) A dimerization hierarchy in the transmembrane domains of the HER receptor family. Biochemistry 46:2010–2019
Zaczek A, Brandt B, Bielawski KP (2005) The diverse signaling network of EGFR, HER2, HER3 and HER4 tyrosine kinase receptors and the consequences for therapeutic approaches. Histol Histopathol 20:1005–1015
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
Pratilas CA, Hanrahan AJ, Halilovic E et al (2008) Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res 68:9375–9383
Lesma E, Grande V, Ancona S et al (2008) Anti-EGFR antibody efficiently and specifically inhibits human TSC2/ smooth muscle cell proliferation: possible treatment options for TSC and LAM. PLoS ONE 3:e3558
Hirata A, Hosoi F, Miyagawa M et al (2005) HER2 overexpression increases sensitivity to gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, through inhibition of HER2/HER3 heterodimer formation in lung cancer cells. Cancer Res 65:4253–4260
Graeff P, Crijns AP, Ten Hoor KA et al (2008) The ErbB signalling pathway: protein expression and prognostic value in epithelial ovarian cancer. Br J Cancer 99:341–349
Rusnak DW, Lackey K, Affleck K et al (2001) The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther 1:85–94
Kim SY, Kim HP, Kim YJ et al (2008) Trastuzumab inhibits the growth of human gastric cancer cell lines with HER2 amplification synergistically with cisplatin. Int J Oncol 32:89–95
Inui T, Asakawa A, Morita Y et al (2006) HER-2overexpression and targeted treatment by trastuzumab in a very old patient with gastric cancer. J Intern Med 260:484–487
Srinivasan R, Leverton KE, Sheldon H et al (2001) Intracellular expression of the truncated extracellular domain of c-erbB-3/HER3. Cell Signal 13:321–330
Kim KK, Lee JJ, Yang Y et al (2008) Macrophage inhibitory cytokine-1 activates AKT and ERK-1/2 via the transactivation of ErbB2 in human breast and gastric cancer cells. Carcinogenesis 29:704–712
Akiyama T, Sudo C, Ogawara H (1986) The product of the human c-erbB–2 gene: a 185-kilo-dalton glycoprotein with tyrosine kinase activity. Science 232:1644–1646
Sakai K, Mori S, Kawamoto T et al (1986) Expression of epidermal growth factor receptors on normal human gastric epithelia and gastric carcinomas. J Natl Cancer Inst 77:1047–1052
Tokunaga A, Onda M, Okuda T et al (1995) Clinical significance of epidermal growth factor (EGF), EGF receptor and c-erbB-2 in human gastric cancer. Cancer 75:1418–1425
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
Sithanandam G, Anderson LM (2008) The ERBB3 receptor in cancer and cancer gene therapy. Cancer Gene Ther 15:413–448
Hayashi M, Inokuchi M, Takagi Y et al (2008) High expression of HER3 is associated with a decreased survival in gastric cancer. Clin Cancer Res 14:7843–7849
Katoh M, Yazaki Y, Sugimura T et al (1993) c-erbB3 gene encodes secreted as well as transmembrane receptor tyrosine kinase. Biochem Biophys Res Commun 192:1189–1197
Lordick F, Bang YJ, Kang YK (2007) HER2-positive advanced gastric cancer: similar HER2-positivity levels to breast cancer. Eur J Cancer 5:271
Cooperative Study Group of HER2 in China (2006) Multicenter study on HER-2/new gene amplification and protein expression in patients with gastric cancer. Chin J Dig 26:657–660
Michimoto K, Akihiro I, Azusa SK et al (2003) Activation of ErbB3–PI3-kinase pathway is correlated with malignant phenotypes of adenocarcinomas. Oncogene 22:1294–1301
Sanidas EE, Filipe MI, Linehan J et al (1993) Expression of the c-erbB-3 gene product in gastric cancer. Int J Cancer 54:935–940
Yamashita K, Sakuramoto S, Kikuchi S et al (2008) Validation of staging systems for gastric cancer. Gastric Cancer 11:111–118
Tateishi M, Toda T, Minamisono Y et al (1992) Clinicopathological significance of c-erbB-2 protein expression in human gastric carcinoma. Surg Oncol 49:209–212
Sasano H, Date F, Imatani A et al (1993) Double immunostaining for c-erbB-2 and p53 in human stomach cancer cells. Hum Pathol 24:584–589
Garcia I, Vizoso F, Martin A et al (2003) Clinical significance of the epidermal growth factor receptor and HER2 receptor in resectable gastric cancer. Ann Surg Oncol 10:234–241
Okegawa T, Kinjo M, Nutahara K et al (2006) Pretreatment serum level of HER2/nue as a prognostic factor in metastatic prostate cancer patients about to undergo endocrine therapy. Int J Urol 13:1197–1201
Kapitanović S, Radosević S, Slade N et al (2000) Expression of erbB-3 protein in colorectal adenocarcinoma: correlation with poor survival. J Cancer Res Clin Oncol 126:205–211
Reschke M, Mihic-Probst D, van der Horst EH et al (2008) HER3 is a determinant for poor prognosis in melanoma. Clin Cancer Res 14:5188–5197
Lee HST, Crocker L, Yao E et al (2008) A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res 68:5878–5887
Narayan M, Wilken JA, Harris LN et al (2009) Trastuzumab-induced HER reprogramming in “resistant” breast carcinoma cells. Cancer Res 69:2191–2194
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Xiu Li Zhang and Yun Sheng Yang equally contributed to this work.
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Zhang, X.L., Yang, Y.S., Xu, D.P. et al. Comparative Study on Overexpression of HER2/neu and HER3 in Gastric Cancer. World J Surg 33, 2112–2118 (2009). https://doi.org/10.1007/s00268-009-0142-z
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DOI: https://doi.org/10.1007/s00268-009-0142-z