Original Article Clinicopathological significance of PTEN and PI3K/AKT signal transduction pathway in non-small cell lung cancer

(1)Int J Clin Exp Pathol 2013;6(10):2112-2120 www.ijcep.com /ISSN:1936-2625/IJCEP1308017. Original Article Clinicopathological significance of PTEN and PI3K/AKT signal transduction pathway in non-small cell lung cancer Fen Yun1, Yongfeng Jia1, Xiuxia Li1, Li Yuan2, Qinnuan Sun1, Huiling Yu1, Lin Shi1, Hongwei Yuan1 Department of Pathology, The First Affiliated Hospital of Inner Mongolia Medical University, Huhhot, 010059, China; 2Shandong Heze Medical College, Heze, Shandong 274000 1. Received August 8, 2013; Accepted September 3, 2013; Epub September 15, 2013; Published October 1, 2013 Abstract: A high frequency of mutations at the PTEN locus has been noticed in carcinoma of lung. However, the role of PTEN alternations and its association with outcome variables in the genesis of lung carcinoma are not understood fully. The purpose of our study was to examine the impact of EGFR, TGF-α, P-AKT and PTEN in the genesis of non-small cell lung cancer (NSCLC). Total numbers of 66 histopathologically confirmed cases of NSCLC and 10 cases of benign control samples embedded with wax were studied. We assessed EGFR, TGF-α and P-AKT by the use of specific antibody through immunohistochemistry as directed by the manufacturer, and detected PTEN expression by in situ hybridization. There were progressive loss of PTEN expression and significant increasing in EGFR, TGF-α, P-AKT expression from benign samples to NSCLC (p<0.05). The overexpression of EGFR, TGF-α, P-AKT and loss of PTEN expression were correlated to differentiation extent of cancer tissue, metastasis of lymph nodes and histological classification. Thus, alteration of EGFR, TGF-α, P-AKT and PTEN are likely important molecular events in pathogenesis and carcinogenesis of NSCLC. Keywords: Non-small cell lung cancer (NSCLC), P-AKT, TGF-α, EGFR, PTEN. Introduction Non-small Cell Lung Cancer (NSCLC) is one of the most formidable health problems in terms of morbidity and mortality facing the mankind today. It is the most common cancer worldwide accounting for 80% of all lung cancer in men and women. Premalignant lesions of tissue show features of epithelial, moderate and severe epithelial dysplasia carry the highest risk for malignant transformation. Identification of high risk premalignant lesions with increased susceptibility to NSCLC and consequent aggressive follow up for early detection and treatment may help in down staging of the cancer and better prognosis [1]. Human NSCLCs show a variety of genetic changes, with different changes in different tumors [2]. PTEN (phosphatase and tensin homolog deleted on chromosome TEN), is a tumor suppressor gene mutated in a variety of human cancers including prostate, breast, brain, endometrial, glioblastoma, and melanoma [3-6]. PTEN expres-. sion has been down regulated in many malignancies including lung carcinoma [7], oral carcinoma colorectal adenocarcinoma [8, 9], breast cancer, colon cancer, and renal cell carcinoma [10, 11]. Earlier investigator showing that induction of apoptosis by low levels of PIP-3 and phosphorylated Akt (P-AKT) has been associated with high levels of PTEN in the genesis of human carcinoma [12, 13]. Conversely, loss of PTEN expression results in increased P-AKT activity and continued cell survival and cell proliferation [14]. Proliferation, apoptosis and differentiation are the fundamental aspects of tumor biology. Earlier studies have reported that mutation and overexpression of epidermal growth factor receptor (EGFR), transforming growth factor-α (TGF-α) and P-AKT in many tumors [15-17]. It cannot be excluded that EGFR, TGF-α and P-AKT protein acts as a marker of a neoplastic transformation threatening in precancerous states..

(2) PTEN and PI3KAKT pathway in non-small cell lung cancer. Figure 1. PTEN showing cytoplasmic expression in NSCLC and benign samples of lung (A: Positive expression of PTEN in lung normal tissue; B: Positive expression of PTEN in lung Squamous carcinoma tissue; C: Positive expression of PTEN in lung adenocarcinoma tissue. Original magnification ×400).. Table 1. Loss of PTEN expression in NSCLC and benign samples Tissue. PTEN +. -. Positive ratio (%). NSCLC. 22. 44. 33.30%. Benign sample. 8. 2. 80%. X2. P-value*. 6.083. 0.014. Note: *Chi-square test.. Table 2. Correlation between PTEN and clinicopathological factors Factors. PTEN -. +~+++. ≤53. 12. 5. >53. 32. 17. Male. 32. 18. Female. 12. 4. X2. P-value*. 0.158. 0.691. 0.66. 0.417. 5.961. 0.015. 4.714. 0.03. 8.727. 0.003. Age. Sex. Lymph node metastasis Positive. 28. 7. Negative. 16. 15. Pathological pattern adenocarcinoma. 20. 4. Squamous carcinoma. 24. 18. Moderate-well. 24. 20. Poor. 20. 2. Differentiation grade. Note: *Chi-square test.. 2113. This study attempts to study the differential expression pattern of EGFR, TGF-α and P-AKT and PTEN protein for its relevance in development and progression of NSCLC. Materials and methods Study population A total of 66 (50 males and 16 females) of histopathologically confirmed cases of NSCLC, and 10 cases of benign control samples of lung were assessed for EGFR, TGF-α, P-AKT and PTEN expression. The age of the patients ranged from 28-77 years with a mean age of 53 years, The patients were diagnosed squamous cell carcinoma (n=42) and adenocarcinoma (n=24), and 41 in advanced stages III/IV, with 25 patients in stages I/II, according to TNM classification. Histopathologic-. Int J Clin Exp Pathol 2013;6(10):2112-2120.

(3) PTEN and PI3KAKT pathway in non-small cell lung cancer. Figure 2. EGFR expression in NSCLC and benign samples of lung (A: Negative expression of EGFR in lung normal tissue; B: Positive expression of EGFR in Squamous carcinoma tissue; C: Positive expression of EGFR in lung adenocarcinoma tissue. Original magnification ×400).. Table 3. EGFR expression in NSCLC and benign samples Tissue. EGFR. X. P-value. 4.367. 0.037. 2. +. -. Positive ratio (%). NSCLC. 46. 20. 69.70%. Benign sample. 3. 7. 30.00%. *. Note: *Chi-square test.. Table 4. Correlation between EGFR and clinicopathological factors Factors. EGFR -. +~+++. X2. P-value*. 0.27. 0.603. 0.047. 0.828. 12.569. 0.001. 0.164. 0.686. 7.03. 0.008. Age ≤53. 6. 11. >53. 14. 35. Male. 16. 34. Female. 4. 12. Sex. Lymph node metastasis Positive. 4. 31. Negative. 16. 15. Pathological pattern adenocarcinoma. 8. 16. Squamous carcinoma. 12. 30. Moderate-well. 18. 26. Poor. 2. 20. Differentiation grade. Note: *Chi-square test.. 2114. ally, the NSCLCs were categorized as well differentiated and moderately differentiated -44 cases and poorly differentiated -22 cases, 35 cases with and 31 cases without lymph node metastasis. The benign samples of lung (males and females), 31-65 years of age (median age, 48 years) were taken as control. The protocol of this study was approved by the Protocol Review Committee and the Bioethics Committee of Inner Mongolia Medical University. PTEN in situ hybridization In order to detect PTEN expression, in situ hybridization assays were per-. Int J Clin Exp Pathol 2013;6(10):2112-2120.

(4) PTEN and PI3KAKT pathway in non-small cell lung cancer. Figure 3. TGF-α expression in NSCLC and benign samples of lung (A: Negative expression of TGF-α in lung normal tissue; B: Positive expression of TGF-α in lung Squamous carcinoma tissue; C: Positive expression of TGF-α in lung adenocarcinoma tissue. Original magnification ×400).. Table 5. TGF-α expression in cytoplasm of NSCLC and benign samples Tissue. TGF-α +. -. NSCLC. 47. 19. 71.20%. Benign sample. 3. 7. 30.00%. X2. P-value*. 4.850. 0.028. Positive ratio (%). Note: *Chi-square test.. Table 6. Correlation between TGF-α and clinicopathological factors Factors. TGF-α -. +~+++. X2. P-value*. 0.142. 0.706. 0. 1. 7.645. 0.006. 1.396. 0.237. 3.695. 0.055. Age ≤53. 6. 11. >53. 13. 36. Male. 14. 36. Female. 5. 11. Positive. 5. 30. Negative. 14. 17. adenocarcinoma. 9. 15. Squamous carcinoma. 10. 32. Moderate-well. 16. 28. Poor. 3. 19. Sex. Lymph node metastasis. Pathological pattern. Differentiation grade. Note: *Chi-square test.. 2115. formed on serial 5 microns thick sections from the original blocks and the TMA block, using a kit for in situ hybridization (MK1276, Boster Biotech Co, Wuhan, China), according to the provider’s specifications as described in detail elsewhere. The poly-A probe, used as an indicator of the preservation of mRNA in the cells (positive control), resulted mainly in dark brown nuclear staining and less in a cytoplasmic one. Immunohistochemical analysis Formalin fixed paraffinembedded tissue blocks were cut in 5 microns thick serial sections. The sections were deparaffinized, rehydrated and rinsed in. Int J Clin Exp Pathol 2013;6(10):2112-2120.

(5) PTEN and PI3KAKT pathway in non-small cell lung cancer. Figure 4. P-AKT immunostaining showing expression in cytoplasm of NSCLC and benign samples of lung (A: Negative expression of P-AKT in lung normal tissue; B: Positive expression of P-AKT in lung Squamous carcinoma tissue; C: Positive expression of P-AKT in lung adenocarcinoma tissue. Original magnification ×400).. Table 7. P-AKT expression in cytoplasm of NSCLC and benign samples Tissue. P-AKT +. -. Positive ratio (%). NSCLC. 50. 16. 75.80%. Benign sample. 2. 8. 20.00%. X2. P-value*. 10.048. 0.002. Note: *Chi-square test.. Table 8. Correlation between P-AKT and clinicopathological factors Factors. P-AKT -. +~+++. X2. P-value*. 0.166. 0.683. 0. 1. 6.662. 0.010. 2.832. 0.092. 4.125. 0.042. Age ≤53. 3. 14. >53. 13. 36. Male. 12. 38. Female. 4. 12. Sex. Lymph node metastasis Positive. 4. 31. Negative. 12. 19. Pathological pattern adenocarcinoma. 3. 21. Squamous carcinoma. 13. 29. Moderate-well. 14. 30. Poor. 2. 20. Differentiation grade. Note: *Chi-square test.. 2116. phosphate buffer saline (PBS). An Immunohistochemical assay for EGFR, TGFα, P-AKT was performed on consecutive paraffin sections using streptavidin-biotin method. Monoclonal mouse antihuman EGFR antibody (ZM0093, Beijing ZSGB Company, China), monoclonal rabbit antihuman TGF-α antibody (ZA254, Beijing ZSGB Company, China) and monoclonal mouse antihuman P-AKT antibody (sc16646, Beijing ZSGB Company, China) were used as primary antibodies respectively. After antigen retrieval slides were incubated with primary antibody, followed by secondary biotinylated antibody. Sections were washed in PBS and then incubated. Int J Clin Exp Pathol 2013;6(10):2112-2120.

(6) PTEN and PI3KAKT pathway in non-small cell lung cancer Scoring method. Table 9. Correlation between EGFR and TGF-α expression EGFR + -. TGF-α +. -. 37 10. 9 10. X2. P-value*. 0.309. 0.012. Note: *Chi-square test.. Table 10. Correlation between EGFR and P-AKT expression EGFR + -. P-AKT + 39 11. 7 9. X2. P-value*. 0.319. 0.022. Note: *Chi-square test.. Table 11. Correlation between P-AKT and TGF-α expression P-AKT + -. TGF-α + 41 6. 9 10. X2. P-value*. 0.421. 0.002. Statistical analysis. Table 12. Correlation between EGFR and PTEN expression. + -. PTEN + 9 13. 37 7. X2. P-value*. -0.443. 0.001. Note: *Chi-square test.. Table 13. Correlation between TGF-α and PTEN expression TGF-α + -. PTEN + 11 11. 36 8. X2. P-value*. -0.331. 0.007. Loss of PTEN expression in NSCLC. Table 14. Correlation between P-AKT and PTEN expression. + -. PTEN + 12 10. 38 6. X2. P-value*. -0.35. 0.004. Note: *Chi-square test.. with streptavidin peroxidase. Finally chromogen Diaminobenzidine (DAB) was used and section were counterstain with hematoxylin.. 2117. Chi-square (X)2 test was performed to find out the possible correlation among EGFR, TGF-α, P-AKT and PTEN and other clinical parameters in NSCLC and benign samples of lung tissue. We used the SPSS ver. 14.0 (SPSS Inc., Chicago, IL, USA), with P<0.05 being considered as statistically meaningful. Results. Note: *Chi-square test.. P-AKT. A total of 5-6 fields from each tissue section were chosen, and 100 cells from each field were counted at final magnification at 400X. With every batch of staining a positive and negative control were used to verify the standard of staining. The percentage of EGFR, TGF-α, P-AKT and PTEN positive cells was calculated independently by two pathologists. The correlations between EGFR, TGFα, P-AKT and PTEN expression and histological grading were studied.. Note: *Chi-square test.. EGFR. Tumors were classified as EGFR, TGFα, P-AKT and PTEN negative (i.e. low expression) if less than 10% of cells displayed positivity. If equal to or greater than 10% of cells were positive for EGFR, TGF-α, P-AKT and PTEN (i.e. high expression) were considered as positive.. The expression of PTEN in benign samples and NSCLC was primarily cytoplasmic, (Figure 1). We observed PTEN expression in 8 of 10 (80%) in benign samples of lung and loss of PTEN expression in 44 of 66 (66.6%) in NSCLC specimens (Table 1).. When we compared the expression of PTEN of NSCLC to benign samples of lung tissue, the loss of frequency of PTEN expression was statistically significant (P<0.001). With regard to tumor characteristics, PTEN expression was associated with. Int J Clin Exp Pathol 2013;6(10):2112-2120.

(7) PTEN and PI3KAKT pathway in non-small cell lung cancer lymph node involvement, histological classification and poor differentiation (Table 2). Immunohistochemical detection of EGFR protein Nuclear immuno reaction for EGFR was considered positive and found in 46/66 cases (69.7%) of NSCLC and 3/10 of benign samples of lung (Figure 2). The result reveals the significant difference between the normal tissue (30%) and cancerous tissue (69.7%) for the EGFR protein (p<0.05). With the progression in lymph node involvement and tumor grade, the rate of EGFR expression significantly increased (Tables 3 and 4). Immunohistochemical detection of TGF-α protein Cytoplasmic and nuclear immuno-reaction for TGF-α was considered positive and found in 47/66 cases (71.2%) of NSCLC and 3/10 of benign samples of lung (Figure 3). In the NSCLC,the overexpression of TGF-α had significant correlation with the metastasis of lymph nodes (Tables 5 and 6). Immunohistochemical detection of P-AKT protein Nuclear immuno reaction for P-AKT was considered positive and found in 50/66 cases (75.8%) of lung carcinoma and 2/10 of benign samples of lung (Figure 4). The result reveals the significant difference between the normal tissue (20%) and cancerous tissue (75.8%) for the P-AKT protein (p<0.05). With the progression in lymph node involvement and tumor grade, the rate of P-AKT expression significantly increased (Tables 7 and 8). The relationship between EGFR, TGF-α, P-AKT and PTEN expression When we compared EGFR, TGF-α, P-AKT and PTEN expression to tumor characteristics, EGFR, TGF-α and P-AKT expression were associated with lymph node involvement, histological classification and poor differentiation. Significant positive correlations (P<0.05) were observed among EGFR, TGF-α and P-AKT overexpression (Tables 9-11), and negative correlations (P<0.05) were found between EGFR, TGFα, P-AKT overexpression with PTEN expression respectively (Tables 12-14). Therefore, we 2118. speculate that tumor prognostic features correlated with EGFR, TGF-α P-AKT and PTEN expression in NSCLC. Discussion Lung cancers make up 14% of all newly diagnosed cancers in the USA today, whereas. Though there are many studies on the etiology of cancer but the exact pathogenesis still remains uncertain. The major etiologic factor in the development of lung cancer is smoking, besides, cultural, and genetic differences, hormonal and possibly infectious factors may also play etiologic roles [18]. The incidence of lung cancer might be due to the cumulative effects of long time exposures to carcinogens, the failings of DNA repair mechanisms and aging [19]. The identification of prognostic and predictive markers is clinically important, because lung cancer is a group of heterogenous diseases with various biological and clinical characteristics. Loss of PTEN function and/or overexpression of growth factors and malfunctions in their signal pathways occur frequently in cancers. EGFR, TGF-α and P-AKT have been studied as predictive markers and prognostic factors in prostate, oral, breast and lung cancers [20, 21]. Earlier investigator showed that expression status of EGFR, TGF-α, P-AKT or PTEN in lung cancer. However, to our knowledge, this is the first study to report that EGFR, TGF-α, and P-AKT expression is inversely correlated with PTEN loss in NSCLC. This observation shows that a mechanism by which EGFR, TGF-α, and P-AKT are upregulated in the development and progression of NSCLC. Such a mechanism would include loss of PTEN activity. The upregulation of EGFR, TGF-α, and P-AKT might reduce the apoptotic induction thereby contributing to the tumorigenesis. The present study reveals that loss of PTEN expression in NSCLC clinical specimens is significantly correlated with EGFR, TGF-α, and P-AKT overexpression. The study also shows that loss of PTEN expression and EGFR, TGF-α, P-AKT overexpression are significantly correlated with NSCLC staging, suggesting that both of the activities may play an important role in NSCLC development and progression. Earlier investigator showed that loss of PTEN increased remarkably according to disease stage and lymph node metastasis [22, 23]. Our study showing that PTEN gene alteration is associated with advanced stage and Int J Clin Exp Pathol 2013;6(10):2112-2120.

(8) PTEN and PI3KAKT pathway in non-small cell lung cancer lymph node metastasis. Our results suggest that PTEN may play an important role in the regulation of tumor progression and metastasis during the development of NSCLC. But the exact role of PTEN in the genesis of NSCLC remains unknown. Studies on PTEN in NSCLC showed frequent genetic alterations and loss of expression but still there are a lot of discrepancies toward the drawing of the final conclusion [24]. Recent study demonstrates that loss of PTEN was associated to up-regulation of the EGFR gene, thus contributing to survival of cancer cells in lung and breast cancers [25, 26]. Our results also showed the strong association of loss PTEN expression with not only EGFR, but also TGF-α, and P-AKT positive expression (p<0.05) in NSCLC.. [6]. [7]. [8]. Acknowledgements This project was supported by science fund for young scholars of Inner Mongolia Medical University (NY2007QN007).. [9]. Disclosure of conflict of interest There is no conflict of interest among all the authors in this study. Address correspondence to: Dr. Yongfeng Jia, Department of Pathology, The First Affiliated Hospital of Inner Mongolia Medical University, NO.1, Northern Tongdao Street, Huhhot, 010059, China. E-mail: yfjia0479@163.com. References [1] [2]. [3] [4]. [5]. Keith RL, Miller YE. Lung cancer chemoprevention: current status and future prospects. Nat Rev Clin Oncol 2013; 10: 334-43. Kadara H, Wistuba II. Field cancerization in non-small cell lung cancer: implications in disease pathogenesis. Proc Am Thorac Soc 2012; 9: 38-42. Salvesen HB, Werner HM, Krakstad C. PI3K Pathway in Gynecologic Malignancies. Am Soc Clin Oncol Educ Book 2013; 2013: 218-21. Cancer Genome Atlas Research Network, Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, Robertson AG, Pashtan I, Shen R, Benz CC, Yau C, Laird PW, Ding L, Zhang W, Mills GB, Kucherlapati R, Mardis ER, Levine DA. Integrated genomic characterization of endometrial carcinoma. Nature 2013; 497: 6773. Daniilidou K, Frangou-Plemenou M, Grammatikakis J, Grigoriou O, Vitoratos N, Kondi-Pafiti A.. 2119. [10]. [11]. [12]. [13]. [14]. [15]. [16]. Prognostic significance and diagnostic value of PTEN and p53 expression in endometrial carcinoma. A retrospective clinicopathological and immunohistochemical study. J BUON 2013; 18: 195-201. Duman BB, Sahin B, Acikalin A, Ergin M, Zorludemir S. PTEN, Akt, MAPK, p53 and p95 expression to predict trastuzumab resistance in HER2 positive breast cancer. J BUON 2013; 18: 44-50. Boespflug A, Couraud S, Bringuier PP, Isaac S, Gérinière L, Perrot E, Edery P, Durieu I, Souquet PJ. Primary lung adenocarcinoma occurring in a PTEN related syndrome (Cowden’s disease): routine EGFR sequencing also highlights two rare somatic mutations S768I and V769L. Lung Cancer 2013; 79: 318-20. Rahmani A, Alzohairy M, Babiker AY, Rizvi MA, Elkarimahmad HG. Clinicopathological significance of PTEN and bcl2 expressions in oral squamous cell carcinoma. Int J Clin Exp Pathol 2012; 5: 965-71. Ghiţă C, Vîlcea ID, Dumitrescu M, Vîlcea AM, Mirea CS, Aşchie M, Vasilescu F. The prognostic value of the immunohistochemical aspects of tumor suppressor genes p53, bcl-2, PTEN and nuclear proliferative antigen Ki-67 in resected colorectal carcinoma. Rom J Morphol Embryol 2012; 53: 549-56. Abdulkareem IH, Blair M. Effects of indomethacin on expression of PTEN tumour suppressor in human cancers. Niger Med J 2013; 54: 1006. Cheng T, Zhang JG, Cheng YH, Gao ZW, Ren XQ. Relationship between PTEN and Livin expression and malignancy of renal cell carcinomas. Asian Pac J Cancer Prev 2012; 13: 2681-5. Li LQ, Li XL, Wang L, Du WJ, Guo R, Liang HH, Liu X, Liang DS, Lu YJ, Shan HL, Jiang HC. Matrine inhibits breast cancer growth via miR-21/ PTEN/Akt pathway in MCF-7 cells. Cell Physiol Biochem 2012; 30: 631-41. Akca H, Demiray A, Tokgun O, Yokota J. Invasiveness and anchorage independent growth ability augmented by PTEN inactivation through the PI3K/AKT/NFkB pathway in lung cancer cells. Lung Cancer 2011; 73: 302-9. Koromilas AE, Mounir Z. Control of oncogenesis by eIF2α phosphorylation: implications in PTEN and PI3K-Akt signaling and tumor treatment. Future Oncol 2013; 9: 1005-15. Dionysopoulos D, Pavlakis K, Kotoula V, Fountzilas E, Markou K, Karasmanis I, Angouridakis N, Nikolaou A, Kalogeras KT, Fountzilas G. Cyclin D1, EGFR, and Akt/mTOR pathway. Potential prognostic markers in localized laryngeal squamous cell carcinoma. Strahlenther Onkol 2013; 189: 202-14. Pannain VL, Morais JR, Damasceno-Ribeiro O, Avancini-Alves V. Transforming growth factor α. Int J Clin Exp Pathol 2013;6(10):2112-2120.

(9) PTEN and PI3KAKT pathway in non-small cell lung cancer. [17]. [18]. [19]. [20]. [21]. [22]. 2120. immunoreactivity. A study in hepatocellular carcinoma and in non-neoplastic liver tissue. Ann Hepatol 2012; 11: 495-9. Berg M, Soreide K. EGFR and downstream genetic alterations in KRAS/BRAF and PI3K/AKT pathways in colorectal cancer: implications for targeted therapy. Discov Med 2012; 14: 20714. Egleston BL, Meireles SI, Flieder DB, Clapper ML. Population-based trends in lung cancer incidence in women. Semin Oncol 2009; 36: 506-15. Grudny J, Kołakowski J, Kruszewski M, Szopiński J, Sliwiński P, Wiatr E, Winek J, Załęska J, Zych J, Roszkowski-Śliż K. Association of genetic dependences between lung cancer and chronic obstructive pulmonary disease. Pneumonol Alergol Pol 2013; 81: 30818. Bettstetter M, Berezowska S, Keller G, Walch A, Feuchtinger A, Slotta-Huspenina J, Feith M, Drecoll E, Höfler H, Langer R. Epidermal growth factor receptor, phosphatidylinositol-3-kinase catalytic subunit/PTEN, and KRAS/NRAS/ BRAF in primary resected esophageal adenocarcinomas: loss of PTEN is associated with worse clinical outcome. Hum Pathol 2013; 44: 829-36. Takeda H, Takigawa N, Ohashi K, Minami D, Kataoka I, Ichihara E, Ochi N, Tanimoto M, Kiura K. Vandetanib is effective in EGFR-mutant lung cancer cells with PTEN deficiency. Exp Cell Res 2013; 319: 417-23. Krohn A, Diedler T, Burkhardt L, Mayer PS, De Silva C, Meyer-Kornblum M, Kötschau D,. [23]. [24]. [25]. [26]. Tennstedt P, Huang J, Gerhäuser C, Mader M, Kurtz S, Sirma H, Saad F, Steuber T, Graefen M, Plass C, Sauter G, Simon R, Minner S, Schlomm T. Genomic deletion of PTEN is associated with tumor progression and early PSA recurrence in ERG fusion-positive and fusionnegative prostate cancer. Am J Pathol 2012; 181: 401-12. Im SA, Lee KE, Nam E, Kim DY, Lee JH, Han HS, Seoh JY, Park HY, Cho MS, Han WS, Lee SN. Potential prognostic significance of p185(HER2) overexpression with loss of PTEN expression in gastric carcinomas. Tumori 2005; 91: 513-21. Panagiotou I, Tsiambas E, Lazaris AC, Kavantzas N, Konstantinou M, Kalkandi P, Ragkos V, Metaxas GE, Roukas DK, Vilaras G, Patsouris E. PTEN expression in non small cell lung carcinoma based on digitized image analysis. J BUON 2012; 17: 719-23. Kim EJ, Jeong JH, Bae S, Kang S, Kim CH, Lim YB. mTOR inhibitors radiosensitize PTEN-deficient non-small-cell lung cancer cells harboring an EGFR activating mutation by inducing autophagy. J Cell Biochem 2013; 114: 124856. Hohensee I, Lamszus K, Riethdorf S, MeyerStaeckling S, Glatzel M, Matschke J, Witzel I, Westphal M, Brandt B, Müller V, Pantel K, Wikman H. Frequent Genetic Alterations in EGFRand HER2-Driven Pathways in Breast Cancer Brain Metastases. Am J Pathol 2013; 183: 8395.. Int J Clin Exp Pathol 2013;6(10):2112-2120.

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