Asian Pacific Journal of Cancer Prevention, Vol 13, 2012 6311 DOI:http://dx.doi.org/10.7314/APJCP.2012.13.12.6311 HER2 and PTEN Simultaneous Deregulation and Biological Behavior of NSCLCs Asian Pacific J Cancer Prev, 13 (12), 6311-6318 Introduction Lung cancer is the leading cause of cancer death worldwide in both men and women, with an estimated 1.4 million deaths each year (Jemal et al., 2011). Non-small- cell lung cancer (NSCLC) accounts for 80-85% of all lung cancer cases (Sher et al., 2008). When feasible, surgical resection remains the single most consistent and successful option for cure. However, close to 70% of patients with lung cancer present with locally advanced or metastatic disease at the time of diagnosis (Molina et al., 2008). The prognosis for patients with NSCLC is strongly correlated with disease stage at the time of diagnosis with 5-year survival rate of about 60% for clinical stage I to less than 5% for clinical stage IV. Improving the survival rate of patients with this disease requires a better understanding 1 Department of Thoracic Surgery, 401 General Military Hospital, 2 Department of Breast Cancer Surgery, Blue Cross Hospital, 3 Department of Pathology, Medical School, University of Athens, 4 Department of Pathology, 417 NIMTS Hospital, 5 2 nd Thoracic Surgery Department, Sotiria Chest Diseases Hospital, Athens, Greece *For correspondence: panagiotouioannis@yahoo.gr Abstract Background: HER2/neu overexpression due to gene amplification is an important factor in breast cancer, modifying the sensitivity to anti-HER2 monoclonal antibody therapy. The clinical significance of HER2 expression in non small cell lung carcinoma (NSCLC) is currently under evaluation. The tumor suppressor gene PTEN negatively regulates the HER2/PI3K/Akt signalling pathway. The purpose of this study was to evaluate the role of simultaneous alteration in HER2 and PTEN protein expression in relation to biological behaviour of NSCLCs. Materials and Methods: Protein expression was determined by immunohistochemistry in sixty-one (n=61) NSCLC cases along with CISH for HER2 gene analysis and detection of chromosome 17 aneuploidy. Patients were followed-up for a period of 34 to 41 months after surgery. Results: HER2 overexpression (2+/3+ score) was detected in 17 (27.9%) patients while loss of PTEN expression was observed in 24 (39.3%) cases, low expression in 29 (47.6%) and overexpression in 8 (13.1%). Simultaneous HER2 overexpression and PTEN low/loss of expression were correlated with metastasis (71.4% vs 36.2% p=0.03). Analysis in the subgroup of 22 patients of pTNM stage III with lymph node status N1 or N2 revealed that there was a relationship between the number of positive regional lymph node groups and simultaneous deregulation of the two genes (p=0.04). Multivariate analysis determined that HER2 overexpression was associated with an increasing risk of developing metastases (OR: 4.3; 95%CI: 1.2-15.9; p: 0.03) while PTEN overexpression was associated with lower risk (OR: 0.1; 95%CI: 0.1, 1.0; p: 0.05). Conclusions: Simultaneous HER2/PTEN deregulation is a significant genetic event that leads to a more aggressive phenotype of NSCLC. Keywords: HER2/neu - PTEN - non-small cell lung carcinoma - gene RESEARCH ARTICLE Impact of HER2 and PTEN Simultaneous Deregulation in Non-small Cell Lung Carcinoma: Correlation with Biological Behavior Ioannis Panagiotou 1 *, Stavros N Georgiannos 2 , Evangelos Tsiambas 3 , Andreas Karameris 4 , Marios Konstantinou 5 , Andreas C Lazaris 3 , Nikolaos Kavantzas 3 , George Vilaras 4 , Efstratios Patsouris 3 of tumor biology and the subsequent development of novel therapeutic strategies. In recent years, a number of molecular markers – including HER2/neu and PTEN – have been tested as predictors for survival and response to cytotoxic chemotherapy and multimodality treatment. The HER2/neu protooncogene is located on the long arm of chromosome 17 (17q21), encoding for a transmembraneous glycoprotein HER2 with intrinsic tyrosine kinase activity and marked sequence homology with the epidermal growth factor receptor (EGFR). Dimerization of HER 2 with an activated EGFR molecule leads to the activation of a signal transduction cascade with subsequent increase in angiogenesis, cell proliferation and metastatic potential, as well as a decrease in apoptosis (Citri and Yarden, 2006). HER2/neu is expressed in a wide variety of human epithelial malignancies including breast,