Mutations and nuclear accumulation of beta-catenin correlate with intestinal phenotypic expression in human gastric cancer

AIMS: Abnormal localization of beta-catenin is frequently observed in human gastric cancers. The aim of the present study was to evaluate relationships among gastrointestinal differentiation phenotypes, beta-catenin localization and mutations of Wnt signalling genes. METHODS AND RESULTS: Seventy-seven regions in 39 gastric adenocarcinomas were classified according to beta-catenin localization and gastric and intestinal phenotypes. Cases with membranous beta-catenin localization showed a gradual decrease from gastric (G) (55% = 6/11) and gastric-and-intestinal-mixed (GI) (17% = 5/29) to intestinal (I) (0% = 0/21) phenotypes, while those with nuclear localization showed a concomitant increase: 18% (2/11), 41% (12/29), 95% (20/21) and 63% (10/16) for G, GI, I and null type (N), respectively (P < 0.001, membranous versus nuclear localization in G, GI through I). Mutations in exon 3 of the beta-catenin gene were found in G (50% = 1/2), GI (67% = 8/12), I (45% = 9/20) and N (0% = 0/10) regions with nuclear beta-catenin localization (GI versus N, P < 0.01; I versus N, P < 0.05). Adenomatous polyposis coli (APC) gene mutations were demonstrated only in GI, I and N types, irrespective of beta-catenin localization. Molecular analysis of these genes revealed 10 tumours to be heterogeneous out of 16 informative cases (62.5%). CONCLUSION: Intestinal phenotypic expression is accompanied by a shift from membranous to cytoplasmic/nuclear accumulation of beta-catenin. In contrast, N-type regions may progress along a different pathway.     

Expression of Wnt-signaling pathway proteins in intraductal papillary mucinous neoplasms of the pancreas: a tissue microarray analysis

Abrogation of the Wnt-signaling pathway is implicated in the carcinogenesis of several malignancies, especially colorectal cancer where up to 90% of cases are thought to have impaired Wnt signaling. It is less frequently involved in conventional ductal pancreatic adenocarcinoma. This pathway has not been explored in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas previously and formed the basis of this study. A tissue microarray of 18 cases of IPMN was stained for proteins involved in the Wnt pathway: adenomatous polyposis coli (APC), pan-beta-catenin, axin 2, glycogen synthase 3alphabeta and 3beta, c-myc, E-cadherin, and cyclin D1. The IPMNs were classified as 8 adenomas, 3 borderline, and 7 cases with carcinoma in situ and/or invasive carcinoma, occurring in 13 females, and the overall age range was 45 to 73 years. Immunohistochemical analysis showed nuclear beta-catenin staining in 7 (39%) of the 18 cases. The cases with nuclear beta-catenin localization included 1 adenoma, 2 borderline IPMN, and 4 carcinomas in situ and/or invasive carcinomas. Seven cases showed absence of APC immunostaining and these included 4 cases with nuclear beta-catenin localization. Fourteen cases displayed marked diffuse up-regulation of c-myc protein, and 12 cases also showed diffuse cyclin D1 protein overexpression. E-cadherin expression was intense and membrane in location (comparable to normal tissue) in 6 of 8 adenomas (no tissue was available in 1 case). Decreased E-cadherin staining was noted in 8 cases where tissue was available for assessment. There was progressive decrease in membrane staining of E-cadherin in 2 of 3 borderline lesions, 1 of 2 carcinomas in situ, and 4 of 5 invasive carcinomas. All other immunostains were either normal in distribution or did not show any correlation with beta-catenin or clinicopathologic parameters. In conclusion, 7 (39%) of 18 cases of IPMN in this study demonstrated abnormal localization of beta-catenin, 4 of which also lacked APC expression. Of 5 carcinomas arising in IPMN, 4 displayed a decrease in E-cadherin expression. There was also a trend for the higher grades of IPMN to show nuclear localization of beta-catenin. These findings suggest that a proportion of cases of IPMN may show abnormalities in the Wnt-signaling pathway with consequent altered expression of downstream related proteins.     

Epstein-Barr virus, beta-catenin, and E-cadherin in gastric carcinomas

Activated beta-catenin is suggested to inhibit NF-kappaB activation, and we previously demonstrated that NF-kappaB nuclear positivity was more frequent in Epstein-Barr virus (EBV)-infected gastric carcinomas. It is controversial that beta-catenin and E-cadherin are prognostic markers in gastric carcinomas. To define a relationship between beta-catenin and EBV, and the prognostic value of beta-catenin and E-cadherin, we analyzed in situ hybridization for EBV-encoded small RNAs, beta-catenin, and E-cadherin immunohistochemistry, and clinicopathological features in 111 gastric carcinomas. EBV infection was detected in seven carcinomas (6.3%); none of seven showed beta-catenin nuclear accumulation, and five out of seven revealed beta-catenin membranous loss or cytoplasmic expression. Eighty cases (72.1%) showed beta-catenin alteration; i.e., loss of membrane staining in 65 (58.6 %), cytoplasmic expression in 35 (31.5%), and nuclear accumulation in 15 (13.5%). E-cadherin alteration was observed in 34 cases (30.6%) and correlated with beta-catenin alteration. On multivariate analysis, the combined immunoexpression group of beta-catenin nuclear accumulation/ E-cadherin alteration and the advanced TNM cancer stage group showed poor patient's survival (p<0.05). In conclusion, beta-catenin activation through nuclear accumulation hardly occurred in EBV-infected gastric carcinomas. The combined immunoexpression pattern of beta-catenin and E-cadherin can be used as a prognostic marker in gastric carcinomas.     

Beta-catenin abnormalities and associated insulin-like growth factor overexpression are important in phyllodes tumours and fibroadenomas of the breast

The aim of this study was to assess the expression of IGF-I and IGF-II in phyllodes tumours and fibroadenomas and to see if there is any correlation between nuclear beta-catenin expression and IGF-I and IGF-II expression in these tumours. In a previous study, it has been shown that Wnt signalling is important in the pathogenesis of phyllodes tumours of the breast. Epithelial Wnt5a overexpression and stromal Wnt2 overexpression were associated with abnormal, nuclear localization of beta-catenin in the stromal cells of these tumours. However, not all tumours with beta-catenin accumulation showed Wnt overexpression. One other possible cause of beta-catenin accumulation is overexpression of insulin-like growth factors (IGFs), as both IGF-I and IGF-II have been shown to stabilize beta-catenin. In this study, 30 fibroadenomas of the breast were assessed for beta-catenin expression using immunohistochemistry and the results were compared with previous data from 119 phyllodes tumours. In situ hybridization was used to assess IGF-I and IGF-II expression in 23 phyllodes tumours and 16 fibroadenomas. Nineteen phyllodes tumours (83%) showed widespread overexpression of IGF-II and 5/23 (22%) showed widespread overexpression of IGF-I. IGF-I expression correlated with nuclear beta-catenin staining in phyllodes tumours. Malignant phyllodes tumours showed no or little IGF-I expression. There was a degree of nuclear beta-catenin expression in the stroma (weak in 33%, moderate in 27%, and strong in 40%) in all fibroadenomas and nuclear beta-catenin staining correlated with IGF-I overexpression. Extensive IGF-II overexpression was also found in the majority of fibroadenomas (12/16). These results support the hypothesis that IGF-I and IGF-II overexpression may be important in the pathogenesis of fibroepithelial neoplasms of the breast and that IGF-I overexpression is likely to be contributing to the nuclear beta-catenin localization observed in the tumours.     

Loss of membranous Ep-CAM in budding colorectal carcinoma cells.

Tumor budding is a histological feature that reflects loss of adhesion of tumor cells and is associated with locoregional metastasis of colorectal carcinoma. Although nuclear localization of beta-catenin is associated with tumor budding, the molecular mechanism remains largely elusive. In this study, we hypothesize that the epithelial cell adhesion molecule (Ep-CAM) is involved in tumor budding. In order to address this question, we performed immunohistochemistry on Ep-CAM using three different antibodies (monoclonal antibodies Ber-ep4 and 311-1K1 and a polyclonal antibody) and a double staining on beta-catenin and Ep-CAM. In addition, Ep-CAM mRNA was monitored with mRNA in situ hybridization. Subsequently, we determined the effect of Ep-CAM staining patterns on tumor spread in rectal cancer. In contrast to the tumor mass, budding cells of colorectal carcinoma displayed lack of membranous but highly increased cytoplasmic Ep-CAM staining and nuclear translocation of beta-catenin. mRNA in situ hybridization suggested no differences in Ep-CAM expression between the invasive front and the tumor mass. Importantly, reduced Ep-CAM staining at the invasive margin of rectal tumor specimens (n=133) correlated significantly with tumor budding, tumor grade and an increased risk of local recurrence (P=0.001, P=0.04 and P=0.03, respectively). These data demonstrate abnormal processing of Ep-CAM at the invasive margin of colorectal carcinomas. Our observations indicate that loss of membranous Ep-CAM is associated with nuclear beta-catenin localization and suggest that this contributes to reduced cell-cell adhesions, increased migratory potential and tumor budding.     

Cyclin D1 overexpression in N-methyl-N′-nitro-N-nitrosoguanidine-induced rat gastric adenocarcinomas

Changes in cell cycle regulation are involved in many human cancers, including gastric cancer. In the present study, cyclin D1 expression and localization were immunohistochemically analyzed in 23 N-methyl-N'-nitro-N-nitrosoguanidine-induced rat gastric adenocarcinomas and compared with findings for beta-catenin. Cyclin D1 nuclear overexpression was more frequently observed in tumors displaying nuclear (4/4=100%) and cytoplasmic (3/4=75%) beta-catenin accumulation than those with membranous (3/15=20%) localization (nuclear vs. membranous, P<0.02). In the former cases it was considered that cyclin D1 was induced with beta-catenin activation; in the latter, a direct or indirect pathway for cyclin D1 accumulation bypassing Wnt pathway might be involved. Cyclin D1 was also found to be accumulated in gastric glands within normal-looking mucosa, these perhaps representing preneoplastic lesions for cancers with membranous beta-catenin accumulation.     

Nuclear accumulation of beta-catenin is a common and early event during neoplastic progression of Barrett esophagus

Our aim was to characterize expression and mutation of beta-catenin in the progression of Barrett esophagus to adenocarcinoma. Immunohistochemical analysis of beta-catenin was performed on paraffin-embedded tissue from 30 cases with adenocarcinomas and premalignant lesions. To determine whether there is a correlation between beta-catenin nuclear accumulation and exon 3 mutation of this gene, mutational analysis by polymerase chain reaction-single-strand conformation polymorphism was performed on DNA extracted from the same 30 adenocarcinomas. As a result, the prevalence of reduced expression of beta-catenin on the membrane, with or without nuclear staining, increased significantly from low-grade (LG) to high-grade (HG) dysplasia. Focal nuclear staining for beta-catenin was present in 19 cases of adenocarcinoma, and nuclear staining was associated significantly with progression from metaplasia to LG dysplasia. In addition, in glands with clear histologic transition from metaplasia to LG dysplasia, nuclear accumulation of beta-catenin was found only in the LG dysplastic areas. No mutation in exon 3 of the beta-catenin gene was detected in adenocarcinomas. These results demonstrate that disturbance of the APC/beta-catenin pathway, as indicated by nuclear accumulation of beta-catenin, is a common and early event during neoplastic progression in Barrett esophagus.     

E-cadherin alterations in atypical lobular hyperplasia and lobular carcinoma in situ of the breast.

Tumor development from an early lesion through to invasive disease is not a clearly defined progression in the breast. Studies of invasive lobular carcinoma have reported mutations, loss of heterozygosity (LOH) and loss of protein expression in epithelial (E)-cadherin, a protein involved in cell adhesion. Our study examines in situ lobular neoplastic lesions without concurrent invasive carcinoma for E-cadherin gene alterations and protein expression, beta-catenin, alpha-catenin and p120-catenin protein expression, and LOH at the chromosome 16q locus, with the goal of determining the events occurring at the stage of lobular neoplasia. In all, 13 atypical lobular hyperplasia lesions and 13 lobular carcinoma in situ lesions from archived cases were examined. E-cadherin sequence alterations were evaluated using single strand conformation polymorphism and DNA sequencing, and PCR-based LOH analysis was carried out for the 16q locus. Using immunohistochemistry, we assessed protein expression. A total of 23 of 24 lesions evaluated by immunohistochemistry were negative for both E-cadherin and beta-catenin protein expression, and 21 of 23 lesions were negative for alpha-catenin. Cytoplasmic (rather than membrane) localization of p120-catenin was observed in 20 of 21 cases. Lobular carcinoma in situ cases were characterized by mutations; however, atypical lobular hyperplasia cases were not. LOH at 16q was an infrequent event. From our study, we conclude that an altered E-cadherin adhesion complex is an early event affecting atypical lobular hyperplasia as well as lobular carcinoma in situ and occurs prior to progression to invasive disease. However, the loss of protein expression is accompanied by E-cadherin DNA alterations in lobular carcinoma in situ but not in atypical lobular hyperplasia. These cases lacking both protein expression and gene alterations suggest that another mechanism is involved, possibly as early as at the hyperplastic stage, causing silencing of the E-cadherin complex.     

Cytoplasmic and/or nuclear staining of beta-catenin is associated with lung metastasis

Beta-catenin is involved in cell motility in the extracellular matrix, and is expressed in normal and neoplastic mesenchymal cells. In order to clarify whether beta-catenin expression in the cytoplasm and/or nucleus is associated with a propensity for pulmonary metastasis in osteosarcoma, the LM8 murine osteosarcoma cell line with a high metastatic potential to the lung was compared with original Dunn cells in terms of the beta-catenin expression level. Both osteosarcoma cell lines lost membrane localization of beta-catenin. However, beta-catenin gene had no mutation in exon 3 by direct sequence analysis. A large number of LM8 cells showed diffuse cytoplasmic and/or nuclear staining of beta-catenin (30.8 per high power field (HPF)), while a much smaller number of Dunn cells showed expression of beta-catenin (7.7 per HPF). Cells with positive staining of beta-catenin were frequently seen at the invasive front and in intravenous tumor deposits within the metastatic lesions to the lung. Thus, LM8 cells express a larger amount of the beta-catenin protein than Dunn cells, as judged by immunoblot analysis. In five resected cases of pulmonary metastasis, translocation of beta-catenin to the cytoplasm and/or nucleus of osteosarcoma cells was detected, although seven primary osteosarcomas cells that did not metastasize for more than five years did not show beta-catenin expression. These data indicate that the cytoplasmic and/or nuclear staining of beta-catenin is a biological marker of metastatic potential of osteosarcoma to the lung. This revised version was published online in July 2006 with corrections to the Cover Date.     

Two case reports of childhood liver cell adenomas harboring beta-catenin abnormalities

The benign epithelial neoplasm liver cell adenoma is rare, especially in childhood. We report 2 such cases, 1 of which was associated with Prader-Willi syndrome. Differential diagnosis of the liver cell adenomas on the basis of histopathologic findings proved difficult and was based on the absence of cellular and nuclear atypia, mitotic activity, and invasive growth. In both cases, immunohistochemical staining demonstrated the nuclear accumulation of beta-catenin, and in 1 case, the tumor cells carried a mutation of the beta-catenin gene. Recently, disregulation of the Wnt/beta-catenin pathway, attributable to abnormalities of the beta-catenin gene, has been reported to be a major event in the development of hepatocellular carcinomas and hepatoblastomas. Our report may be the first to describe the beta-catenin abnormalities in childhood liver cell adenoma. These findings imply that abnormalities of beta-catenin can be an early initiating event in human liver tumorigenesis.     

Disparate E-cadherin mutations in LCIS and associated invasive breast carcinomas.

AIMS: The relation between lobular carcinoma in situ (LCIS) and invasive breast cancer is unresolved. In an attempt to establish whether LCIS is a precursor of invasive cancer the mutational status and the expression of E-cadherin was analysed in LCIS and associated invasive breast carcinoma in 23 patients. METHODS: Foci of LCIS and associated invasive carcinoma were individually microdissected from tissue from 23 patients. Exons 4-16 of the E-cadherin gene were analysed using single strand conformation polymorphism (SSCP); protein expression and the localisation of E-cadherin and beta-catenin were assessed with the use of immunohistochemistry. RESULTS: Immunohistochemistry revealed a lack of expression of E-cadherin and beta-catenin in most LCIS samples and invasive foci. In all but four cases, the staining pattern was identical in the LCIS and associated invasive areas. When E-cadherin was absent, beta-catenin was also undetected, suggesting a lack of expression of alternative classic cadherin members in these lesions. Coincident E-cadherin mutations in LCIS and associated invasive carcinoma were not identified in this series of patients. However, mutational analysis of E-cadherin in multiple foci of carcinoma in situ surrounding an invasive lesion provided evidence to support ductal carcinoma in situ as a precursor of invasive ductal carcinoma. CONCLUSION: These data support the hypothesis that LCIS is not a precursor of invasive breast carcinoma but a marker of increased risk of developing invasive disease.     

β-Catenin expression and allelic loss at <Emphasis Type="Italic">APC</Emphasis> in sporadic colorectal carcinogenesis

beta-catenin is involved in E-cadherin-mediated cell adhesion, intracellular signal transduction, and also interacts with adenomatous polyposis coli (APC) protein. We previously found that 31% of colorectal adenomas and 84% of carcinomas showed reduced membranous staining of beta-catenin, while 46% of adenomas and 79% of carcinomas displayed beta-catenin nuclear expression. Importantly, a reciprocal relationship between reduced membranous and increased nuclear beta-catenin expression was demonstrated in the development from adenoma to carcinoma. To clarify whether this relates to an abnormality of the APC gene ( APC), we have now studied allele loss in microdissected tissues from 74 adenomas and 21 carcinomas (sporadic cases, previously immunostained for beta-catenin) by analysis of the microsatellites D5S346, D5S82 and D5S299. Fifty-five tumors (57.8%) showed allele loss at APC (no difference between adenomas and carcinomas). Thirty-one of these 55 (31/55, 56.4%) displayed both increased nuclear localization and reduced membranous staining of beta-catenin, and thirteen tumors (13/55, 23.6%) manifested either nuclear expression without changes in membranous expression or reduced membranous staining without nuclear expression (9 and 4 cases, respectively), while 11 (11/55, 20.0%) preserved normal membranous expression. Adenomas and carcinomas showing both nuclear and reduced membranous expression of beta-catenin, compared with those with normal membranous expression, tended to show allele loss ( P<0.01). In addition, 24 (24/95, 25.6%) tumors showed a change in the pattern of beta-catenin expression, but did not exhibit allele loss. These results suggest that although there may be a number of mechanisms responsible for changes in beta-catenin expression in colorectal tumors, dysfunction of APC may be the major cause of this phenomenon.     

Nuclear Accumulation of Mutated β-Catenin in Hepatocellular Carcinoma Is Associated with Increased Cell Proliferation

Inappropriate activation of the Wnt pathway resulting from beta-catenin gene alterations has recently been implicated in the development of hepatocellular carcinoma (HCC). To explore the in vivo effects of mutated beta-catenin, HCC specimens from 32 patients carrying one or several tumors were screened for somatic mutations in exon 3 of the beta-catenin gene, and the expression and subcellular localization of beta-catenin was studied by immunohistochemistry. Missense mutations or interstitial deletions in beta-catenin exon 3 were detected in 12 of 35 (34%) HCC samples. After immunostaining, most tumors exhibited increased membranous and/or cytoplasmic expression of beta-catenin compared with adjacent nontumoral liver. Strong nuclear accumulation of beta-catenin was observed either focally or uniformly in 15 of 35 (43%) tumor specimens, but not in cirrhotic nodules or dysplastic liver cells in adjacent liver. Aberrant nuclear expression of beta-catenin was significantly associated with the presence of mutations in the beta-catenin gene (P < 0.005). Moreover, nuclear beta-catenin staining correlated significantly with increased Ki-67 proliferative index in tumor (P < 0.001) and seemed to be associated with poor outcome in patients with HCC. In conclusion, our data indicate that activation of the Wnt/beta-catenin pathway in HCC results mainly from somatic mutations in the beta-catenin gene and may promote tumor progression by stimulating tumor cell proliferation.     

The expression pattern of beta-catenin in mesothelial proliferative lesions and its diagnostic utilities

beta-Catenin is a component of the E-cadherin-catenin cell adhesion complex. It plays an important role in the Wnt/wg pathway, which conveys critical signals for cell proliferation and transformation. The beta-catenin mutation is an important event in the progression of a number of malignancies. In this study, we evaluated the immunohistochemical (IHC) pattern of beta-catenin in a spectrum of mesothelial lesions. Sixty-five formalin-fixed, paraffin-embedded blocks from 54 serous effusions and 11 pleural biopsies were examined. These cases consisted of 33 invasive mesotheliomas, 9 early mesotheliomas (with negative radiologic finding), so-called mesotheliomas in situ, and 23 reactive mesothelial proliferations. A distinct membranous and/or submembranous staining pattern was seen in 23 cases with normal and reactive mesothelium. In contrast, reduced membranous and/or submembranous antibody staining and markedly increased ectopic cytoplasmic and nuclear staining was seen in 26 cases of 33 mesotheliomas. Seven of 9 early mesotheliomas showed increased ectopic cytoplasmic and/or nuclear stain. On the basis of our findings, identification of beta-catenin staining pattern offers a useful marker in the diagnosis of mesothelial lesions and may help identify neoplastic change.     

Genetic alterations in gastric adenomas of intestinal and foveolar phenotypes.

Gastric adenomas are unusual neoplasms that can constitute one of the direct precursors to gastric adenocarcinoma. Most gastric adenomas are comprised of polypoid projections of dysplastic epithelium with at least focal intestinal-type differentiation (containing goblet cells and/or Paneth cells), whereas adenomas comprised entirely of dysplastic foveolar-type epithelium are rare. It has been shown that nearly all intestinal-type adenomas arise in association with background intestinal metaplasia and gastric atrophy, approximately 40% harbor high-grade dysplasia, and nearly one fourth progress to adenocarcinoma. In contrast, foveolar-type adenomas tend to occur in otherwise normal, nonatrophic gastric mucosa and rarely harbor high-grade dysplasia or carcinoma. Potential differences in the genetic alterations between intestinal-type and foveolar-type gastric adenomas have not been systematically studied. We investigated 11 intestinal-type and 7 foveolar-type gastric adenomas (all from patients without familial adenomatous polyposis) for alterations in APC (using 5q allelic loss assays and direct DNA sequencing of the mutation cluster region), beta-catenin (using direct DNA sequencing of the phosphorylation region in exon 3), K-ras (using direct DNA sequencing of codons 12 and 13), and microsatellite instability (MSI; using fluorescent-based PCR amplification of a standard panel of 5 microsatellite markers). Overall, 10 of 11 (91%) intestinal-type adenomas harbored at least one detectable genetic alteration, whereas only 3 of 7 (43%) of foveolar-type adenomas did (P =.047). However, no statistically significant differences in any particular genetic alteration were found. Among intestinal-type adenomas, APC alterations were present in seven (64%), high-level MSI in three (27%), and K-ras mutations in two (18%). Among foveolar-type adenomas, APC alterations were present in three (43%) and a K-ras mutation in one of six amplifiable polyps (17%). Neither APC nor MSI correlated with the size of the adenoma, but K-ras mutations were found only in lesions of > or = 1 cm. beta-catenin mutations were not present in any gastric adenoma, irrespective of the presence or absence of APC alterations. These results suggest that the types and frequencies of genetic alterations occurring in gastric and colorectal adenomas are similar. Although intestinal-type and foveolar-type gastric adenomas display divergent biologic behavior, the specific genetic events accounting for these differences in morphology and biologic behavior are unclear.     

Reduced expression of alpha-catenin, beta-catenin, and gamma-catenin is associated with high cell proliferative activity and poor differentiation in non-small cell lung cancer

AIMS: To investigate the expression of catenins (alpha, beta, and gamma) in non-small cell lung carcinoma (NSCLC) and its relation to clinicopathological factors and prognosis. METHODS: The expression of catenins was analysed immunohistochemically in 261 patients with resected NSCLC, diagnosed between 1978 and 1996 in eastern Finland: The cell proliferation index of the tumours was analysed by means of an image analyser. The staining results were compared with clinicopathological characteristics and survival. RESULTS: Normal catenin staining was found significantly more often in adenocarcinomas than in squamous cell carcinomas or anaplastic/large cell carcinomas. Reduced staining of alpha-catenin, beta-catenin, and gamma-catenin was related to poor differentiation of the tumour. The tumours with reduced staining of beta-catenin or gamma-catenin often had higher cell proliferation activity. Nuclear staining of beta-catenin and gamma-catenin was found in 16 (7%) and 29 (13%) cases, respectively. This nuclear staining correlated directly with increased cell proliferation and inversely with membranous staining. In survival analyses the predictors of overall and disease free survival were stage and tumour type. The expression of catenins did not affect survival. CONCLUSIONS: The expression of alpha-catenin, beta-catenin, and gamma-catenin is related to histological type and differentiation in NSCLC, although catenins have no independent prognostic value. However, this study supports the important role of the nuclear accumulation of beta-catenin and gamma-catenin in highly proliferative cells.