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Alteration in key oncoprotein expression in gastric adenocarcinoma – An immunohistochemical study

1 Department of Pathology, University College of Medical Sciences and Guru Teg Bahadur Hospital, New Delhi, India
2 Department of Surgical Disciplines, All India Institute of Medical Sciences, New Delhi, India

Date of Submission10-May-2021
Date of Decision01-Jul-2021
Date of Acceptance02-Jul-2021
Date of Web Publication28-Jan-2022

Correspondence Address:
Pragya Jain,
Department of Pathology, University College of Medical Sciences and Guru Teg Bahadur Hospital, Tahirpur Road, GTB Enclave, Dilshad Garden, New Delhi - 110 095
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_760_21

 > Abstract 

Objective: This study was conducted to evaluate the frequency and clinicopathologic correlates of human epidermal growth factor receptor 2 (HER-2)/neu and betacatenin (BC) oncoproteins in gastric adenocarcinoma and to seek correlation if any between their expression status.
Materials and Methods: This cross-sectional analytical immunohistochemistry (IHC) study was performed on 50 cases of gastric adenocarcinoma. HER-2/neu immunoexpression was scored as per criteria by Ruschoff et al. as positive (3+), equivocal (2+), and negative (1+, 0). Aberrant BC expression was categorized as nuclear, cytoplasmic, and reduced membranous immunoexpression. Protein expression results of both oncoproteins were correlated with conventional clinicopathological parameters. Correlation between immunoexpression profiles of both proteins was also analyzed. P <0.05 was considered statistically significant.
Results: HER-2/neu positivity (2 + and 3+) was seen in 94% of the cases; almost 60% had strong (3+) expression. All cases showed aberrant BC immunoexpression (any pattern) except 2 cases that revealed negative expression (a form of aberrant immunoexpression) and were removed from analysis due to a very small number. The pattern of BC expression was as follows: nuclear expression (38%), cytoplasmic expression (82%), reduced membranous expression (96%), no staining (4%) cases. HER-2/neu expression correlated with age. No significant correlation was found between any of the 2 oncoprotein immunoexpression and other clinicopathological parameters (P > 0.05). Concordance between protein expression of HER-2/neu and BC was seen in >93% cases, however, the correlation was not significant.
Conclusion: HER-2/neu and BC oncoprotein expression are frequently dysregulated in gastric adenocarcinomas. The significance of pathways involving HER-2/neu and BC in gastric carcinogenesis should be explored.

Keywords: Betacatenin, gastric adenocarcinoma, human epidermal growth factor receptor 2/neu

How to cite this URL:
Jain P, Wadhwa N, Diwaker P, Joshi MK, Mishra K. Alteration in key oncoprotein expression in gastric adenocarcinoma – An immunohistochemical study. J Can Res Ther [Epub ahead of print] [cited 2022 Nov 29]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=336702

 > Introduction Top

Gastric carcinoma (GC) is the fifth most common malignancy worldwide. Its geographic distribution is heterogeneous with the majority of cases occurring in East Asian countries. At present, it accounts for 5.6% of all cancers and 7.7% of all cancer-related deaths across both genders worldwide.[1],[2] India is a low-risk country for GC, however, disease burden is likely to increase due to the high prevalence of Helicobacter pylori infection. It remains asymptomatic in the early stages, with the majority of patients presenting in the advanced stage when the prognosis is poor.

In the WHO classification of digestive tumors 2018, there was a shift from pure morphologic classification to treatment guiding molecular classification. Based on genome sequencing and molecular profiling, the cancer genome atlas has divided gastric cancers into 4 subtypes, namely Epstein–Barr virus positive, microsatellite unstable, genomic stable, and chromosomal instable.[3] To effectively guide the oncologist about potential therapeutic targets and prognosis, it becomes imperative to know about molecular mechanisms of gastric carcinogenesis.

HER-2/neu is a protooncogene encoding a transmembrane tyrosine kinase receptor. Its amplification and protein overexpression drive exponential growth of tumor cells. Directed molecular therapy against HER-2/neu by trastuzumab (monoclonal antibody against HER-2/neu) in patients with advanced gastric/gastroesophageal carcinoma has been found to increase the overall survival from 11.1 to 13.8 months.[4] The frequency of HER-2/neu protein expression in GC detected by immunohistochemistry (IHC) varies from 3.9% to 53.4%.[5] In a metanalysis on the prognostication of HER-2/neu in 11,860 GC patients, Jorgenson and Hersom pooled 38 original study articles and found a significant association between HER-2/neu status with poor survival and clinicopathologic parameters in 72% of studies.[5] Limited literature on HER-2/neu expression in GC is available from the Indian subset of patients.

Betacatenin (BC) is a multifunctional protein that regulates E-cadherin-mediated cell adhesion and Wnt (Int/Wingless) mediated cell signaling depending on its localization. Under healthy circumstances, it is subjected to ubiquitin proteasomal degradation, and hence, there is no intracellular localization.[6],[7] Normal gastric tissue shows only membranous BC expression. Dysregulation of BC either by Wnt pathway activation or E-cadherin loss leads to reduced membranous and aberrant intracellular expression. Earlier studies on its frequency, intracellular localization, and clinicopathologic correlation in GC have shown variable results.[6]

Despite a huge burden of GC in India, there is a paucity of literature on the above markers from our country. We undertook this study to evaluate the expression of both markers in GC and correlate their expression status with conventional clinicopathologic parameters.

 > Materials And Methods Top

This cross-sectional analytical study was done in the Department of Pathology and Surgery at the tertiary care center, Delhi. IHC for BC and HER-2/neu was conducted on 50 (22 gastrectomies and 28 biopsies) histologically confirmed cases of GC which were included in the study. Cases with a history of prior chemotherapy, insufficient material in the block, and incomplete medical records were excluded from the study. Clinicopathologic details of all the cases as per College of American Pathologist guidelines were noted on structured proforma.[8] The Institutional Ethical Committee clearance was obtained before the commencement of the study.

Protocol for IHC for betacatenin and human epidermal growth factor receptor 2/neu

Immunoexpression of HER-2/neu and BC was assessed in 4-μ thick formalin-fixed paraffin-embedded representative sections using monoclonal mouse antibody to HER-2/neu (Biogenex, MU134-UCE; 1:20 dilution) and BC antibody (Biocare Medical, CM406C; 1:200 dilution). The standard procedure of IHC using a universal polymer kit was followed. After bringing sections to water, antigen retrieval was done using 0.01 M sodium citrate buffer at pH 6.0 in a decloaking chamber at 95°C for 30 min. Endogenous peroxidase activity was blocked using 3% H2O2 for 30 min. After washings with tris buffer, a snipper (BS966G) was applied for 30 min to prevent nonspecific antibody uptake. Slides are blot dried and incubated overnight with respective primary antibody at 4°C. The next day after 3 serial washes with tris buffer sections are incubated with secondary antibody (MACH 1 mouse probe; UP537G) for 30 min followed by HRP polymer (MACH 1; MRH538G) for 30 min. Diaminobenzidine (DAB) chromogen (3,3'-DAB) was used till the desired color was reached. Sections were counterstained with hematoxylin (10 dips). Immunoexpression of both proteins was evaluated by two independent pathologists to check for reproducibility under the light microscope. Normal gastric epithelium in a case of chronic gastritis was taken as a positive control.

Evaluation of human epidermal growth factor receptor 2/neu overexpression

HER-2/neu scoring was done using the scoring system proposed by Ruschoff et al.[9] [Table 1].
Table 1: Detailed criteria of human epidermal growth factor receptor-2/neu immunoexpression in gastric adenocarcinoma in both resection specimen and biopsies

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Evaluation of betacatenin staining

Criteria for BC immunoexpression are still not defined. Under normal circumstances, BC is expressed in the cell membrane. We defined aberrant BC immunoexpression as loss of membranous expression (LOM), cytoplasmic, nuclear, and compound expression. Membranous reactivity was considered preserved if >70% of tumor cells displayed membranous immunoreactivity, else it was labeled as loss of membranous expression.[7] Nuclear expression was labeled as positive when ≥10% of cells displayed immunoreactivity.[7] Cases with ≥10% cells displaying cytoplasmic immunoreactivity were considered positive for cytoplasmic expression. Cases displaying aberrant expression in all cellular components were considered as showing compound expression. H score was calculated for cases showing nuclear positivity similar to carcinoma breast.[10] It was the summative score derived by multiplying each score intensity with percentage of cells showing positivity.

SPSS statistical soft ware no. 20. Armonk, NY: IBM corp was used for statistical analysis. Chi-square/Fisher exact test was applied for statistical calculations. Protein expression results were correlated with conventional clinicopathological parameters. We also sought a correlation between immunoexpression of the above two oncoproteins. P <0.05 was considered statistically significant.

 > Results Top

The mean age of presentation of GC patients was 53.4 years with no gender predilection (male: female = 1.1:1). Clinicopathologic characteristics of all the cases are tabulated in [Table 2]. Twelve cases showed H. pylori-related gastritis. Intestinal metaplasia was seen in 6 cases and dysplasia was identified in 16 cases. There was no history of familial gastric cancer or any other malignancy in any case.
Table 2: Characteristics of patients with gastric adenocarcinoma

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Assessment of human epidermal growth factor receptor 2/neu expression

Results of HER-2/neu revealed ≥2+ expression seen in 94% (47/50) cases. Of these, 63.8% (30/47) showed 3+ intensity [Figure 1]a and [Figure 1]b. The correlation of HER-2/neu expression with conventional clinicopathological parameters is described in [Table 3]. A majority (70.2%) with HER-2/neu expression ≥2+ were older than 50 years as compared to 30.4% of HER-2/neu negative. This association between HER-2/neu expression and age >50 years was statistically significant (P = 0.013). However, the difference between HER-2/neu expression between genders was not significant. Diffuse/poorly cohesive histology was seen in 61.7% HER-2/neu ≥2+ cases. Almost 95% of cases with HER-2/neu overexpression invaded beyond mucosa (≥T2), 89% had moderate to poor grade of differentiation (≥G2). All cases with lymphovascular invasion, nodal metastasis, and dysplasia had ≥2+ HER-2/neu expression, however, the differences were not significant. No correlation was found between HER-2/neu expression and Lauren/WHO classification of GC, neural invasion, stage and grade of GC (P > 0.05).
Figure 1: H and E stained section (×40) shows (a) strong distinct membranous positivity (3+) and (b) moderate complete membranous positivity (2+) in gastric adenocarcinoma

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Table 3: Correlation between human epidermal growth factor receptor-2/neu and betacatenin immunoexpression with clinicopathologic parameters

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Assessment of betacatenin expression

All except 2 cases showed aberrant BC immunoexpression (any form) with the following expression pattern: reduced membranous expression (96%), cytoplasmic expression (82%), nuclear expression (38%), and compound expression (34%) [Figure 2]a, [Figure 2]b, [Figure 2]c. [Table 3] shows the correlation of BC immunoexpression with clinicopathologic parameters. Cases with dysplasia had significantly reduced membranous BC immunoexpression in comparison to cases without dysplasia (P = 0.05). There was no significant difference with respect to clinicopathologic features when correlated with other 2 patterns of BC staining (cytoplasmic and nuclear). H score >150 was seen in three cases. Cases with high H score showed a significant correlation with high tumor grade (≥2) (P = 0.017).
Figure 2: Hematoxylin and Eosin (H & E) stained section shows (a) normal gastric epithelium with membranous BC staining. (positive control) (b) GC with strong nuclear and cytoplasmic BC immunoexpression (c) GC with loss of membranous immunoexpression (40x)

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Almost ≥95% of cases with any form of aberrant BC (reduced membranous, cytoplasmic, nuclear) staining showed HER-2/neu overexpression, however, the difference was not significant.

 > Discussion Top

The prognosis of GC is dismal in the majority of the cases because of its late presentation. During the early course, the disease remains occult and patients usually present in the advanced stage when palliative therapy becomes the only available option. Day by day expanding knowledge of molecular mechanisms behind carcinogenesis and their prognostic implication has opened up many nonsurgical therapeutic avenues that may offer survival benefits to these patients. We studied the expression of two oncoproteins in GC, a topic on which meager data are available from India.[7],[11]

We found 60% (30/50) of GC cases to be overexpressing HER-2/neu (3+) while 34% (17/50) were equivocal (2+). HER-2/neu overexpression ranges from 3.9% to 53.4% in gastric adenocarcinoma patients.[5] The factors that are responsible for this wider range of frequency may include the type of antibody used, sample size, different scoring criteria, and tumor biology in different ethnic populations. We observed higher frequency by following the scoring criteria of overexpression as validated by Ruschoff et al.[9] Despite modest sample size, our study holds relevance due to the paucity of literature on HER-2/neu overexpression in Indian patients. The mortality of GC in developing countries like India is high due to its late presentation and limited access to oncologic services. HER-2/neu overexpression/amplification halves the overall survival of patients in GC (12.7 months vs. 6.6 months).[12] By imparting targeted therapy to these 60% HER-2/neu overexpressed cases, significant improvement in overall survival and progression-free survival can be seen.

The prognostic impact of HER-2/neu status and clinicopathological variables has been a matter of debate. Jorgensen and Hersom in their systemic review of 39 studies (multivariate and univariate) revealed that association of HER-2/neu positivity and poor survival or clinicopathological variable could be established in 72% (28/39) studies.[5] In our study, we found HER-2/neu positivity (≥2+) more in cases with adverse clinicopathologic factors (moderate to poor grade, advanced tumor, nodes and metastases [TNM] stage, nodal metastasis), however, the correlation was not significant. A significant correlation was found between HER-2/neu ≥2+ and age ≥50 years. Liu et al. in their study on 122 Chinese GC patients found a statistically significant correlation between HER-2/neu positivity and age >60 years (P = < 0.05).[13]

In the present study, HER-2/neu overexpression was seen in 100% (18/18) intestinal histology and 90% (29/32). Increasing HER-2/neu immunoexpression was noted in intestinal type in comparison to diffuse type by Barros-Silva et al.[14] Rakhshani et al. found significant correlation of HER-2/neu positivity with poor grade (P = 0.015), intestinal histology (P = 0.041), and larger tumor size (P = 0.038) and a trend toward lymph nodal involvement (P = 0.071).[15] The data on the prognostic impact of HER-2/neu status are conflicting due to differences in sample size, scoring schemes, and the difference in sampling advancing edge of the tumor. Although we did not find any significant correlation of HER-2/neu overexpression with many clinicopathologic factors, its therapeutic implication should not be ignored.

BC has a dual role in cell adhesion through E-cadherin and transcriptional activation through the Wnt signaling pathway. Reduced membranous expression was the most common aberrant BC expression pattern seen in 96% (48/50) followed by cytoplasmic accounting for 82% (41/50). Other authors too have observed reduced/loss of membranous expression as the most common aberrant pattern followed by ectopic intracellular localization.[16],[17] Grabsch et al. in their study on 401 gastrectomies done for GC found reduced membranous to complete loss of membranous expression in expression in 86.5% (347/401), diffuse cytoplasmic expression in 13.2% (53/401), and ectopic nuclear localization in 6.5% (26/401) cases.[17] Variability in the frequency of BC expression pattern is due to the lack of standard BC assessment criteria and possible heterogeneous expression. They have segregated aberrant membranous expression as moderately reduced/highly reduced/complete loss of expression as well as ectopic cytoplasmic and nuclear expression were graded positive or negative. Sun et al. have observed 69% of cases of GC to have aberrant BC expression.[7] Differences in sample size and type of antibody used and ethnic variation may contribute to this variability. A much higher frequency of aberrant BC expression in our study suggests the possibility of a greater role of the BC pathway in gastric carcinogenesis in Indian patients.

The association of aberrant BC staining and clinicopathologic parameters was also studied. We found a positive association of aberrant BC with worse clinicopathologic parameters. A significant correlation was seen between reduced membranous pattern and dysplasia (P = 0.05). A trend toward diffuse/poorly cohesive histology was seen with cytoplasmic BC staining. Ramesh et al. had also reported a significant correlation of reduced membranous expression with diffuse histology and poor grade of differentiation (P < 0.05).[16] Meta-analysis of 3404 advanced gastric patients showed a consolidated association of abnormal BC expression with tumor progression. Authors had asserted significant correlation of abnormal BC with diffuse histology (odds ratio [OR] =1.98, 95% confidence interval [CI]: 1.19–3.29), lymph node metastasis (positive vs. negative: OR = 2.00, 95% CI: 1.44–2.77), distant metastasis (positive vs. negative: OR = 2.69, 95% CI: 1.35–5.38), and poor differentiation (G3/G4 vs. G1/G2: OR = 2.68, 95% CI: 1.66–4.34).[6] We did not find any correlation between BC expression and clinicopathologic variables, which could be due to our limited sample size.

In breast carcinoma, the role of the H score for semiquantitative estimation of estrogen receptor and risk stratification is well documented.[10] The optimum cutoff for H score in estrogen receptor assessment is not well defined. Various authors have used different cutoff points to evaluate its prognostic role.[18] None of the reported studies had analyzed the role of H score in GC. In our study, we found a significant correlation with nuclear H score >150 and poor differentiation, however, the numbers are small to draw any conclusion and more studies are needed.

Cases with dysplasia had >2+ HER-2/neu (100%), cytoplasmic BC (87.5%), and reduced membranous (81.5%) immunoexpression. A significant correlation was found between reduced membranous BC expression and dysplasia (P = 0.05) but not with HER-2/neu and other aberrant patterns of BC expression. However, few authors have reported the association of dysplasia with HER-2/neu overexpression, nuclear BC expression, and reduced membranous BC expression.[19],[20] We observed a higher frequency of HER-2/neu and aberrant BC expression in dysplasia suggesting their role in the evolution of gastric carcinogenesis.

In our study, all the cases with HER-2/neu overexpression had any form of aberrant BC expression. Yamaguchi et al. in their review have given an insight on the possible role of BC/Wnt crosstalk in mediating HER-2/neu resistance.[21] In addition, it is seen that HER-2/neu overexpression-mediated phosphorylation of BC leads to aberrant cell-to-cell or cell-matrix interactions and impaired E-cadherin-related function. Ougolkov et al. observed higher hepatic metastasis in cases with simultaneous HER-2/neu overexpression and altered BC expression.[22] High concordance between these oncoproteins in our study reiterates the need for more literature evaluating this aspect. We acknowledge few limitations of our study such as limited sample size and lack of follow-up, and we could not analyze equivocal cases by fluorescence in situ hybridization. Our study holds relevance in view of its potential relevance to gastric carcinogenesis and therapeutic targeting. To the best of our knowledge, this is the first study from Northern India analyzing the role of two major pathways in gastric carcinogenesis.

 > Conclusion Top

We found a high frequency of HER-2/neu overexpression (almost 60%) and aberrant BC expression (96%) in the north Indian cohort suggesting that the above two pathways play a major role in gastric carcinogenesis. Nevertheless, we did not find any significant correlation of these oncoproteins with adverse histological factors (TNM stage, histology, grade, lymphovascular invasion, nodal metastasis). However, HER-2/neu directed targeted therapy could benefit a large number of Indian patients who may have higher HER-2/neu overexpression. Aberrant BC might have a role in early gastric carcinogenesis due to its significant correlation with dysplasia.

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Conflicts of interest

There are no conflicts of interest.

 > References Top

Rawla P, Barsouk A. Epidemiology of gastric cancer: Global trends, risk factors and prevention. Prz Gastroenterol 2019;14:26-38.  Back to cited text no. 1
The Globocan Cancer Observatory. Available form: https://gco.iarc.fr/today/data/factsheets/cancers/7-Stomach-fact-sheet.pdf. [Last accessed on 2021 May 02].  Back to cited text no. 2
Wang Q, Liu G, Hu C. Molecular classification of gastric adenocarcinoma. Gastroenterology Res 2019;12:275-82.  Back to cited text no. 3
Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 2010;376:687-97.  Back to cited text no. 4
Jørgensen JT, Hersom M. HER2 as a prognostic marker in gastric cancer – A systematic analysis of data from the literature. J Cancer 2012;3:137-44.  Back to cited text no. 5
Li LF, Wei ZJ, Sun H, Jiang B. Abnormal β-catenin immunohistochemical expression as a prognostic factor in gastric cancer: A meta-analysis. World J Gastroenterol 2014;20:12313-21.  Back to cited text no. 6
Sun GY, Wu JX, Wu JS, Pan YT, Jin R. Caveolin-1, E-cadherin and β-catenin in gastric carcinoma, precancerous tissues and chronic non-atrophic gastritis. Chin J Cancer Res 2012;24:23-8.  Back to cited text no. 7
College of American Pathologists – Cancer Protocol Templates. Available from: https://documents.cap.org/protocols/Stomach_4.2.0.0.REL_CAPCP.pdf. [Last accessed on 2020 Jun 30].  Back to cited text no. 8
Rüschoff J, Hanna W, Bilous M, Hofmann M, Osamura RY, Penault-Llorca F, et al. HER2 testing in gastric cancer: A practical approach. Mod Pathol 2012;25:637-50.  Back to cited text no. 9
Detre S, Saclani Jotti G, Dowsett M. A “quickscore” method for immunohistochemical semiquantitation: Validation for oestrogen receptor in breast carcinomas. J Clin Pathol 1995;48:876-8.  Back to cited text no. 10
Sekaran A, Kandagaddala RS, Darisetty S, Lakhtakia S, Ayyagari S, Rao GV, et al. HER2 expression in gastric cancer in Indian population – An immunohistochemistry and fluorescence in situ hybridization study. Indian J Gastroenterol 2012;31:106-10.  Back to cited text no. 11
Hechtman JF, Polydorides AD. HER2/neu gene amplification and protein overexpression in gastric and gastroesophageal junction adenocarcinoma: A review of histopathology, diagnostic testing, and clinical implications. Arch Pathol Lab Med 2012;136:691-7.  Back to cited text no. 12
Liu X, Wang X, Wang B, Ren G, Ding W. HER2 gene amplification by fluorescence in situ hybridization (FISH) compared with immunohistochemistry (IHC) in 122 equivocal gastric cancer cases. Appl Immunohistochem Mol Morphol 2016;24:459-64.  Back to cited text no. 13
Barros-Silva JD, Leitão D, Afonso L, Vieira J, Dinis-Ribeiro M, Fragoso M, et al. Association of ERBB2 gene status with histopathological parameters and disease-specific survival in gastric carcinoma patients. Br J Cancer 2009;100:487-93.  Back to cited text no. 14
Rakhshani N, Kalantari E, Bakhti H, Sohrabi MR, Mehrazma M. Evaluation of HER-2/neu overexpression in gastric carcinoma using a tissue microarray. Asian Pac J Cancer Prev 2014;15:7597-602.  Back to cited text no. 15
Ramesh S, Nash J, McCulloch PG. Reduction in membranous expression of beta-catenin and increased cytoplasmic E-cadherin expression predict poor survival in gastric cancer. Br J Cancer 1999;81:1392-7.  Back to cited text no. 16
Grabsch H, Takeno S, Noguchi T, Hommel G, Gabbert HE, Mueller W. Different patterns of beta-catenin expression in gastric carcinomas: Relationship with clinicopathological parameters and prognostic outcome. Histopathology 2001;39:141-9.  Back to cited text no. 17
Wang Y, Ma X, Wang Y, Liu Y, Liu C. Comparison of different scoring systems in the assessment of estrogen receptor status for predicting prognosis in endometrial cancer. Int J Gynecol Pathol 2019;38:111-8.  Back to cited text no. 18
Ieni A, Barresi V, Giuffrè G, Caruso RA, Lanzafame S, Villari L, et al. HER2 status in advanced gastric carcinoma: A retrospective multicentric analysis from Sicily. Oncol Lett 2013;6:1591-4.  Back to cited text no. 19
Sun L, Chen F, Shi W, Qi L, Zhao Z, Zhang J. Prognostic impact of TAZ and β-catenin expression in adenocarcinoma of the esophagogastric junction. Diagn Pathol 2014;9:125.  Back to cited text no. 20
Yamaguchi H, Chang SS, Hsu JL, Hung MC. Signaling cross-talk in the resistance to HER family receptor targeted therapy. Oncogene 2014;33:1073-81.  Back to cited text no. 21
Ougolkov A, Yamashita K, Bilim V, Takahashi Y, Mai M, Minamoto T. Abnormal expression of E-cadherin, beta-catenin, and c-erbB-2 in advanced gastric cancer: Its association with liver metastasis. Int J Colorectal Dis 2003;18:160-6.  Back to cited text no. 22


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