Beta-catenin expression in human cancers.

Cell-cell adhesion in tissue is mainly regulated by homotypic interaction of cadherin molecules, which are anchored to the cytoskeleton via cytoplasmic proteins, including alpha- and beta-catenin. Although we previously demonstrated that alpha-catenin is crucial for cadherin function in vivo, little is known about the role of beta-catenin. We examined the expression of beta-catenin in human carcinoma samples along with normal tissue (esophagus, stomach, and colon) by immunostaining using our antibody for beta-catenin. Normal epithelium strongly expressed beta-catenin. However, beta-catenin expression was frequently reduced in primary tumors of the esophagus (10 of 15, 67%), stomach (9 of 19, 47%), and colon (11 of 22, 50%). From an immunoprecipitation study, we found that beta-catenin forms a complex with E-cadherin not only in the normal epithelium but also in cancerous tissues. In coexpression patterns of E-cadherin and beta-catenin, 43 (77%) of the 56 tumors showed a similar expression of both molecules, whereas the other 13 tumors (23%) showed positive staining for E-cadherin and reduced expression of beta-catenin. These findings suggest that beta-catenin forms a complex with E-cadherin in vivo and down-regulation of beta-catenin expression is associated with malignant transformation.     

Expression of Immunoreactive E-Cadherin Adhesion Molecules in Human Cancers

E-cadherin (E-CD), a Ca(2+)-dependent adhesion molecule, plays a major role in the maintenance of intercellular junctions in normal epithelial cells in most organs. The expression of E-CD in human carcinoma samples (esophagus, stomach, and breast) was investigated using immunohistochemical staining, which was performed on surgical specimens using a monoclonal antibody for human E-CD. E-cadherin was strongly expressed in all normal epithelium examined. However E-CD expression in primary tumors of esophagus (11 of 15: 73%), stomach (5 of 20: 25%), and breast (9 of 20: 45%) was reduced, and 68% of these (esophagus: 8 of 11, stomach: 4 of 5, breast: 5 of 9) displayed heterogeneous E-CD expression. In some tumor cells with reduced E-CD expression, E-CD molecules were located in the cell cytoplasm. These results indicate that there are human cancer cells in which E-CD-related intercellular adhesion is impaired.     

Expression of adhesion proteins E-cadherin, alpha-catenin, beta-catenin and gamma-catenin is different in T1 and T2 breast tumours

BACKGROUND: Breast cancer is the most common malignancy in women. Although an increasing number of patients with breast cancer are being cured by surgery, a considerable number of patients suffer relapse in the form of metastases after surgery. E-cadherin and catenins have documented roles in breast cancer progression. Mammography is supposed to decrease breast cancer mortality by detecting tumours while they are small and before they have reached a clinically detectable stage.Aim: In the present study, we wanted to evaluate whether there are differences in expression patterns of adhesion proteins, shown to be crucial in the metastatic process, between small tumours detected by mammography and clinically detected large tumours. METHODS: Expression of E-cadherin, alpha-catenin, beta-catenin and gamma-catenin was analysed using immunohistochemistry methods in 86 invasive breast carcinomas detected by mammography and compared with 90 clinically palpable invasive breast carcinomas. RESULTS: In the group of tumours detected by mammography (86 samples), reduced expression of E-cadherin was observed in 12 (14%) samples. Reduced expression of alpha-catenin was observed in four (4.6%) samples, and three (3.5%) samples showed reduced expression of beta-catenin. All samples showed strong expression of gamma-catenin. When expression patterns of these proteins were evaluated in 90 clinically detected tumours, we observed reduced expression of E-cadherin in 58 (64.4%) samples, 12 (13.3%) samples showed reduced expression of alpha-catenin, while nine (10%) samples showed reduced expression of beta-catenin. Strong expression of gamma-catenin was detected in all tumours also in this group.Statistical analyses revealed a highly significant difference in expression of E-cadherin (p<0.001). However, no statistically significant differences were observed in expression of alpha-catenin (p = 0.081) and beta-catenin (p = 0.092) between the two groups of tumours. CONCLUSION: Results indicate that T1 breast tumours harbour less alterations in E-cadherin-catenin complexes and therefore are probably less likely to disseminate, and patients probably have a better prognosis than if tumours are diagnosed as T2.     

Expression and distribution of insulin-like growth factor-1 receptor in human carcinomas

The insulin-like growth factor-1 receptor (IGF1-R) is a cellular receptor overexpressed in many tumor cell lines and in some human tumors that seems to play a critical role in transformation, tumorigenicity, and metastasis. To date, a comprehensive evaluation of tissue distribution of IGF1-R in human carcinomas from different anatomical sites has been lacking. Using stage-oriented human cancer tissue microarrays, we studied IGF1-R expression and distribution in a group of 152 human carcinomas from a variety of anatomical sites and from 63 normal tissues through immunohistochemistry. The tumors included carcinomas from breast (8), ovary (9), endometrium (7), esophagus (5), stomach (7), pancreas (7), liver (4), colon (10), kidney (14), bladder (17), prostate (11), head and neck (31), salivary glands (8), lung (13), and skin (1). Formalin-fixed, paraffin embedded tissues of each case were immuno-stained using the avidin-biotin peroxidase method and an anti-IGF1-R rabbit polyclonal antibody. High-membranous IGF1-R staining was observed in 7 of 8 (87.5%) breast carcinomas, in 9 of 9 (100%) ovarian carcinomas, in 7 of 7 (100%) endometrial carcinomas, in 5 of 7 (71.1%) gastric carcinomas, in 4 of 7 (57.1%) pancreatic carcinomas, in 9 of 10 (90%) colon adenocarcinomas, in 11 of 13 (84.6%) lung carcinomas, in 6 of 11 (54.5%) prostatic adenocarcinomas, and in 17 of 17 (100%) transitional cell carcinomas of the bladder. Only a minority of squamous cell carcinomas of the head and neck and esophagus (34), salivary gland tumors (5), and renal cell carcinomas (14) were IGF1-R positive. This study demonstrates the overexpression of IGF1-R across a wide variety of human carcinomas of glandular or transitional cell origin.     

Downregulation of TNF-related apoptosis-inducing ligand (TRAIL)/Apo2L in Barrett's esophagus with dysplasia and adenocarcinoma.

TRAIL/Apo2L is a CD95 ligand-related member of the TNF family that initiates apoptosis in immune and neoplastic cells after binding to specific surface receptors. The authors previously reported a specific topographic pattern of TRAIL expression in the normal colonic mucosa and the loss of TRAIL expression in tubular adenomas as well as in most colon carcinomas. Therefore, they hypothesized that similar changes may occur during the malignant transformation of Barrett's esophagus. The aim of this study was to compare TRAIL/Apo2L expression in normal gastroesophageal (GE) junction, Barrett's esophagus with and without dysplasia, and associated adenocarcinoma. Immunohistochemical evaluation of TRAIL expression was performed on formalin-fixed paraffin-embedded sections from 29 GE junction/esophageal biopsies, 20 gastric biopsies, 6 esophagectomies, 2 small bowel resection specimens, and 5 colon biopsies. The expression was graded semiquantitatively on a 4-point scale (0-3). TRAIL was expressed in the foveolar epithelium of the histologically normal GE junctional mucosa and stomach as well as in the normal intestinal epithelium, with maximal expression in the surface epithelium. TRAIL was always detected in Barrett's metaplasia (21/21, 100%), and the overall expression was similar to that of the columnar portion of the normal GE junction (8/8, 100%). TRAIL was rarely and weakly (1+) expressed in Barrett's esophagus with dysplasia (3/18, 16.7%) and adenocarcinoma (1/10, 10.0%) (P<0.001). Similarities in the topographic pattern of TRAIL expression in the normal GE junction, stomach, small intestine, and colon suggest a common function of TRAIL throughout the gastrointestinal tract. These results show that the downregulation of TRAIL is associated with development of dysplasia in Barrett's esophagus. Thus, the immunohistochemically detected downregulation of TRAIL expression appears to be a promising indicator of dysplasia in Barrett's esophagus.     

Alterations of E-cadherin, α-catenin and β-catenin expression in neuroendocrine tumors of the gastrointestinal tract

Neuroendocrine tumors (NETs) of the gastrointestinal tract comprise a heterogeneous group of neoplasms arising from the diffuse neuroendocrine system. These tumors strongly differ from each other on the basis of different pathogenetic, clinical, functional, histological, and prognostic patterns. Previous studies have shown that abnormal and reduced expression of the E-cadherin/catenin complex in several human cancers is associated with tumor dedifferentiation, advanced clinical stages, and poor survival rate. We assessed correlations between the expression of E-cadherin and catenins, Ki-67, and the following clinicopathological factors: age, embryological site of origin, size, histological growth pattern, the depth of penetration into the intestinal wall, and the presence of metastasis. In this study, reduction of membranous E-cadherin expression to a variable degree was detected in more than two-thirds (42 of 51) of gastrointestinal NETs (19 foregut, 8 midgut, and 24 hindgut) belonging to the complete neuroendocrine neoplastic spectrum [18 well-differentiated NETs, 22 well-differentiated neuroendocrine carcinomas (NECs), and 11 poorly differentiated NECs]. The reduction of E-cadherin expression was concomitant with the reduction of alpha-catenin (44 of 51) and beta-catenin (35 of 51) expression. Our immunohistochemical analysis demonstrated significant differences of percentage of membranous positive cells of E-cadherin, alpha-catenin, or beta-catenin between normal tissues and well-differentiated NETs (P=0.0038, P=0.004, and P=0.0329, respectively), well-differentiated NECs (P<0.001, P<0.001, and P<0.001, respectively) and poorly differentiated NECs (P=0.0002, P<0.0002, and P=0.0002, respectively). Among the gastrointestinal NETs, there were significantly more positive cells of E-cadherin, alpha-catenin, or beta-catenin in well-differentiated NETs than well-differentiated NECs (P=0.0006, P=0.0065, and P=0.0001, respectively) or poorly differentiated NECs (P=0.0053, P=0.0041, and P<0.001, respectively). MIB-1 labeling index generally showed a low proliferative activity in well-differentiated NETs (0.49+/-0.37) and well-differentiated NECs (0.662+/-0.66). A high proliferation rate was observed in poorly differentiated NECs (41.518+/-16.59). MIB-1 labeling index was significantly higher in poorly differentiated NECs than well-differentiated NETs and well-differentiated NECs (P<0.0001 and P<0.0001, respectively). E-cadherin, alpha-catenin, and beta-catenin expression were correlated significantly with transmural tumor invasion (P<0.0001, P=0.0001, and P<0.0001, respectively) and with size (P=0.0013, P=0.0001, and P<0.0001, respectively). These results indicate that the alteration in the E-cadherin/catenin expression may be involved in the growth and progression of gastrointestinal NETs.     

Expression of E-cadherin and p53 proteins in human soft tissue sarcomas.

OBJECTIVE: To investigate the expression of E-cadherin in human soft tissue sarcomas and its potential relationship to p53 alterations. DESIGN: Tissue sections of 91 soft tissue sarcomas were analyzed by immunohistochemistry for E-cadherin and p53 proteins. Sixty-one tumors were investigated further by the application of the polymerase chain reaction technique and a direct sequence analysis procedure of exons 5 through 8 in the p53 gene. SETTING: Tertiary-care teaching hospital. PATIENTS: Ninety-one patients with soft tissue tumor were treated surgically. Thirteen of these patients had tumors with epithelial differentiation. RESULTS: E-Cadherin was expressed at the cell-cell boundaries in 11 samples (12%): 9/13 (69%) with and 2/78 (3%) without histologic evidence of epithelial elements. Other sarcomas were completely negative for E-cadherin. Overexpression of p53 was detected in 30 cases (33%), 7 of which also demonstrated mutations in the p53 gene. The frequencies of p53 abnormalities in tumors with and without epithelial components were 8% and 37%, respectively. No association was established between E-cadherin immunoreactivity and p53 abnormalities (P =.13). Tumor grade strongly correlated with p53 alterations (P =.01), but not with E-cadherin expression (P =.07). CONCLUSIONS: These data support the involvement of p53 alterations in the pathogenesis of soft tissue sarcomas. The lack of E-cadherin expression in these tumors, with the exception of lesions showing epithelial differentiation, indicates that E-cadherin is not an important factor involved in cell-cell adhesion in sarcomas. It is, however, suggested that E-cadherin may play a role in the development and/or maintenance of epithelial architecture in sarcomas, regardless of p53 status.     

Molecular characteristics of differentiated-type gastric carcinoma with distinct mucin phenotype: LI-cadherin is associated with intestinal phenotype

Gastric carcinomas (GC) are classified into four phenotypes on the basis of the mucin expression profile: G type (gastric or foveolar phenotype), I type (intestinal phenotype), GI type (intestinal and gastric mixed phenotype) and N type (neither gastric nor intestinal phenotype). Immunohistochemistry was used to examine the expression of epidermal growth factor receptor (EGFR), E-cadherin, liver-intestine (LI)-cadherin, CD44v9 and p53 and correlation of these molecules with mucin phenotype and tumor stage was evaluated. Overexpression of EGFR and LI-cadherin, reduced expression of E-cadherin and abnormal expression of p53 were observed more frequently in advanced GC than in early GC. Among I-type GC, overexpression of EGFR and reduced expression of E-cadherin were observed more frequently in advanced tumors than in early tumors. Among G-type GC, reduced expression of E-cadherin was significantly associated with advanced tumors. With respect to the relationship between mucin phenotype and expression of cancer-related molecules, overexpression of LI-cadherin was observed more frequently in I-type (12/25, 48.0%) than in G-type (1/14, 7.1%) GC. I-type GC tended to express LI-cadherin more frequently than GI-type GC. These results provide insights into the molecular characteristics of the distinct mucin phenotype of differentiated-type GC and suggest that LI-cadherin may contribute to the biological behavior of I-type GC.     

端粒酶基因在人肿瘤组织中的表达

目的 探讨端粒酶基因表达与肿瘤恶性表型及其与端粒酶活性的关系;评价端粒酶基因表达检测在肿瘤诊断中的价值。方法 用原位杂交的方法检测端粒酶基因ｈＴＲ和ｈＴＲＴ在７８例人觉癌组织,２０例癌前病变,２８例良性病变中的表达及分布情况。结果 ７８例癌中ｈＴＲ阳性率为８５％（６６／７８）,ｈＴＲＴ阳性率为８２％（６４／７８）;在癌旁组织中ｈＴＲ、ｈＴＲＴ的表达阳性率分别为３％（２／７８）、５％（４／７８）;２     

Expression of E-cadherin, alpha- & beta-catenin, and CD44V6 and the subcellular localization of E-cadherin and CD44V6 in normal epidermis and basal cell carcinoma

Basal cell carcinoma (BCC) of the skin is a locally invasive, rarely metastasizing epithelial tumor. In the current study, the expression of E-cadherin, alpha- and beta-catenin and CD44V6 in normal epidermis and on BCC cells were investigated. A significantly reduced expression of alpha-catenin and CD44V6 and a slightly reduced expression of E-cadherin on BCC cells were observed compared with the overlying epidermis. Immunoelectron microscopy was used to investigate whether the decreased expression of E-cadherin and CD44V6 was due to either an absence or downregulation of specific membrane structures or due to an overall downregulation of these adhesion molecules in all membrane structures in BCC. E-cadherin and CD44V6 were expressed in adherens junctions, desmosomes, and complex interdigitating membrane structures both in normal epidermis and in BCC. A quantitative analysis showed that only a percentage of desmosomes was stained. In addition, the effect of pro-inflammatory cytokines, such as interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), was investigated in biopsy specimens of normal skin and BCC, using a biopsy culture system and immunohistochemistry. The expression of E-cadherin and CD44V6 was not significantly decreased after culturing BCC or normal skin biopsy specimens for 48 hours with or without recombinant human (rHu)IFN-gamma or rHuTNF-alpha. It may be concluded that the decreased expression of both E-cadherin and CD44V6, observed in light microscopy, was not attributable to the absence of specific specialized structures in BCC and most likely also not caused by downregulation by local cytokines, but rather by generic downregulation of both of these adhesion molecules during malignant transformation.     

Role of E-cadherin, alpha-, beta-, and gamma-catenins, and p120 (cell adhesion molecules) in prolactinoma behavior.

E-cadherin/catenin complex regulates cellular adhesion and motility and is believed to function as an invasion suppressor system. In a number of cancers, abnormal and reduced expression of E-cadherin/catenin complex is associated with tumor invasion and metastasis. Prolactinomas show frequent invasion on the surrounding structures, despite their histologically benign nature. Furthermore, gender-based differences in endocrine and surgical findings are found in patients with prolactinoma. To understand biological factors governing prolactinoma behavior, this study analyzed the expression of E-cadherin; alpha-, beta-, and gamma-catenins; p120; and cell proliferation marker MIB-1 labeling index in 13 invasive tumors (9 in men, 4 in women), 26 noninvasive tumors (4 in men, 22 in women), and 8 normal anterior pituitaries by immunohistochemistry. Immunostaining of E-cadherin; alpha-, beta-, and gamma-catenins; and p120 showed a membranous pattern of reactivity and generally stronger in normal pituitaries than in prolactinomas. Expression of E-cadherin and beta-catenin was significantly lower in invasive than in noninvasive prolactinomas (P <.002 and P <.005, respectively), and reduced expression of E-cadherin and beta-catenin was more frequent in invasive than in noninvasive prolactinomas (P <.001 and P <.05, respectively); in contrast, gamma-catenin expression showed higher in invasive than in noninvasive prolactinomas (P <.05). Expression of E-cadherin was significantly lower in macroprolactinomas than in microprolactinomas (P <.01), and decreased expression of E-cadherin and beta-catenin predicted high MIB-1 expression (P <.05). Moreover, the expression of E-cadherin and beta-catenin was significantly lower in macroprolactinomas in men than in those in women (P <.01 and P <.02, respectively). No statistical correlations were observed between expression of alpha-catenin, p120, and clinicopathologic features. In conclusion, the reduction of E-cadherin and beta-catenin expression was related to invasiveness and proliferative status of prolactinomas and correlated with the more aggressive behavior of prolactinomas in men compared with in women.     

Immunoreactive E-cadherin, alpha-catenin, beta-catenin, and gamma-catenin proteins in hepatocellular carcinoma: relationships with tumor grade, clinicopathologic parameters, and patients' survival

We evaluated the immunohistochemical expression status of E-cadherin, alpha-catenin, beta-catenin, and gamma-catenin, and the relationship with tumor grade, clinicopathologic parameters, and patients' survival, in 107 surgically resected hepatocellular carcinoma (HCC), using a semiquantitative scoring system. These molecules were largely located at the cell membrane of HCC cells. Compared with expression in nontumorous liver, E-cadherin showed underexpression, whereas alpha-, beta-, and gamma-catenins showed overexpression in most HCC. E-cadherin expression significantly correlated inversely with HCC histological grade, being the highest in well-differentiated HCC. In contrast, alpha-, beta-, and gamma-catenins' expression significantly correlated positively with HCC grade, being the highest in poorly differentiated HCC. Significant positive correlations were found between gamma-catenin high expression and capsular invasion or presence of satellite nodules, and between beta-catenin high expression and vascular invasion. Kaplan-Meier examination of patients' survival indicated that HCC patients with underexpression of E-cadherin, alpha-catenin, and gamma-catenin, and patients with overexpression of beta-catenin, had poor survival rates. These results suggest that E-cadherin is downregulated while the 3 catenins are upregulated in HCC, that E-cadherin expression inversely correlates with HCC grade while the 3 catenins' expression positively correlates with HCC grade, and that HCC patients with downregulation of E-cadherin, alpha-catenin, and gamma-catenin and HCC patients with upregulation of beta-catenin have poor prognosis.     

Overexpression of cyclin D1 occurs in both squamous carcinomas and adenocarcinomas of the esophagus and in adenocarcinomas of the stomach.

Increased expression of the cyclin D1 gene frequently occurs in human squamous carcinomas of the esophagus. However, the expression of cyclin D1 has not been previously examined in detail in adenocarcinomas of the esophagus or stomach. Therefore, we examined, in parallel, the expression of cyclin D1 in both squamous and adenocarcinomas of the esophagus and in adenocarcinomas of the stomach. The level of expression of the cyclin D1 protein was assessed by immunohistochemistry in 39 esophageal and 34 gastric carcinomas and correlated with clinical and pathology parameters. Within the esophagus, 71% of the squamous carcinomas and 64% of the adenocarcinomas were positive for increased cyclin D1 nuclear staining. For adenocarcinomas of the stomach, the overall positive rate was 47%; in the gastric cardia, the rate was 44%, and in other regions of the stomach, it was 50%. In esophageal and gastric adenocarcinomas of the intestinal type, increased expression of cyclin D1 was seen in 70% of the samples, whereas with the diffuse type only 13% were positive (P < .01). Tumors from patients older than the median age of 67 years were more frequently positive than tumors from patients younger than 67 years (74% v 42%, respectively) (P < .01). Positive staining was also seen more frequently in well and moderately differentiated tumors than in poorly differentiated tumors (74% v 49%, respectively) (P < .05). Cytoplasmic staining for cyclin D1 was noted in 22% of the tumors, of various types. Therefore, increased expression of cyclin D1 frequently occurs in both adenocarcinomas and squamous carcinomas of the esophagus, and in adenocarcinomas of the stomach. The increased expression in adenocarcinomas is especially frequent in the intestinal-type lesions.     

E-cadherin expression in sporadic gastric cancer from Mexico: exon 8 and 9 deletions are infrequent events associated with poor survival

Aberrant expression and mutation of E-cadherin is frequent in gastric carcinoma (GC) especially of the diffuse type. The frequency of CDH1 (gene encoding E-cadherin) mutation in populations with high incidence of diffuse GC and its prognostic significance is unknown. One hundred seventy-seven gastrectomies from Mexican mestizo patients with intestinal (53), mixed (55), or diffuse (69) GC were included. In addition, 101 endoscopic biopsies from patients with GC not subjected to surgery were analyzed. Immunohistochemistry against wild-type E-cadherin (clone 36) and against 2 mutation-specific antibodies (MSA) recognizing mutant CDH1 lacking exon-8 (del 8) or exon-9 (del 9) were performed. Staining was correlated with histotype, tumor node metastasis stage, and follow-up. Abnormal or absent E-cadherin expression (clone 36) was identified in 84% GC, predominantly in diffuse or mixed tumors (P = 0.004) in advanced stages (P = 0.003). No survival differences at 1 and 2 years were observed among patients showing normal, abnormal, or absent wild type E-cadherin expression. Overall reactivity with the MSA was observed in 10 (5.6%) patients who were treated with surgery. In 140 patients, dead from the disease or alive with the disease, the survival at 1 and 2 years was 37% versus 17% and 14% versus 0 for patients without and with del 8/9 positivity, respectively (log rank P = 0.01). Biopsies from patients with inoperable-GC (101) rendered 5 (4.95%) with del 8 or 9 immunoreactivity. Abnormal E-cadherin expression is frequent in GC. However, exon 8 or 9 deletions were observed in only 5.3% tumors in this series from Mexico, at a lower rate than previously published, but associated with a worse prognosis.     

Molecular characterization of undifferentiated-type gastric carcinoma

As the great majority of gastric cancers develop histologically differentiated, and a significant proportion of differentiated-type carcinomas progress to become undifferentiated, both histological types are likely to share several common genetic abnormalities, such as p53 mutations at advanced stages. However, a subset of gastric cancers develop as undifferentiated carcinomas, including signet-ring cell carcinoma and poorly differentiated adenocarcinoma, and the molecular pathogenesis of this tumor type remains largely unknown. To characterize the molecular features of undifferentiated-type gastric carcinomas that developed as undifferentiated-type, we examined for p53, APC, and epithelial (E)-cadherin gene mutations, microsatellite alterations including loss of heterozygosity (LOH) and microsatellite instability (MSI), and hypermethylation of the E-cadherin gene promoter in 26 early undifferentiated gastric carcinomas, consisting of 14 signet-ring cell carcinomas and 12 poorly differentiated adenocarcinomas. E-cadherin expression was evaluated immunohistochemically. p53 mutations were detected in only one poorly differentiated adenocarcinoma sample (3.8%; 1/26), whereas no APC or E-cadherin mutations were found. LOH was present only at D8S261 on the short arm of chromosome 8 in 2 of 14 (14%) informative tumors, both of which were poorly differentiated adenocarcinomas, and MSI was not observed in any of the tumors. No signet-ring cell carcinomas have been found to carry gene mutations or microsatellite alterations. In contrast, hypermethylation of the E-cadherin promoter occurred in 69% (18/26) of the tumors; 57% (8/14) of signet-ring cell carcinomas, and 83% (10/12) of poorly differentiated adenocarcinomas, and was significantly associated with loss or reduced expression of E-cadherin. Thus, whereas tumor suppressor gene mutation, LOH, and MSI were less common in undifferentiated-type early gastric carcinomas, epigenetic inactivation of E-cadherin via promoter hypermethylation may be an early critical event in the development of undifferentiated tumors.     

Abnormal alpha-catenin expression in invasive breast cancer correlates with poor patient survival

AIMS: alpha-Catenin is a member of the E-cadherin-catenin family of adhesion molecules whose role is essential for the function of the E-cadherin complex. In this study, we have evaluated the expression of alpha-catenin but also of the other catenins (beta-, gamma- and p120-catenin) and E-cadherin in invasive breast cancer and statistically analysed these expressions with known clinicopathological parameters, c-erbB-2 oncoprotein expression and patient survival. METHODS AND RESULTS: Abnormal E-cadherin and beta-catenin expression, especially loss of expression, was associated with lobular histological type of breast carcinomas (P=0.03 and P=0.01, respectively). Abnormal E-cadherin and alpha-catenin expression was associated with high histological grade ductal carcinomas (P=0.01 and P=0.03, respectively). Abnormal E-cadherin and beta-catenin expression was correlated with lymph node metastases (P=0.02 and P=0.05, respectively), while abnormal alpha- and beta-catenin were correlated with the advanced stage of the disease (P=0.04 and P=0.05, respectively). Abnormal p120-catenin expression was associated with loss of PR (P=0.008). Survival analysis demonstrated a statistically significant association between abnormal alpha-catenin expression and poor patient survival (P=0.02). When survival analysis was performed according to the different patterns of abnormal expression, statistically significant associations were seen between cytoplasmic alpha- and beta-catenin expression and poor survival (P=0.006 and P=0.04, respectively). CONCLUSIONS: alpha-Catenin, especially its cytoplasmic expression, seems to be a more sensitive prognostic marker than the other members of the E-cadherin complex in invasive breast cancer.     

Prognostic value of the preserved expression of the E-cadherin and catenin families of adhesion molecules and of beta-catenin mutations in synovial sarcoma

This study addresses the immunohistochemical expression of the E-cadherin and catenin families and mutations of the beta-catenin gene detected by PCR-SSCP in synovial sarcoma. Immunohistochemical analysis was performed for 72 cases, with follow-up data available on 62. The prognostic value of the expression of these proteins was evaluated. Reduced immunoreactivity for E-cadherin and alpha-catenin was significantly correlated with a poor survival rate (p=0.0040 and 0.0053, respectively). According to multivariate analysis, low AJC stage (stages I and II: p<0.0001), the preservation of alpha-catenin expression (p=0.0001), and a low necrotic rate (<50%: p=0.0139) were independent favourable prognostic factors. Widespread aberrant staining of beta-catenin protein within cytoplasm and/or nuclei was observed in 28 cases (38.9%) and was significantly correlated with poor survival (p=0.0122). In addition, there was a trend towards a correlation between widespread aberrant staining of beta-catenin and the MIB-1 labelling index (p=0.0535). Mutational analysis of exon 3 of the beta-catenin gene was performed for 49 cases. Nucleotide sequencing analysis revealed that four (8.2%) contained point mutations (three in codon 32, GAC to TAC; one in codon 37, TCT to TTT). Survival data were available for three out of four cases with beta-catenin mutations; two of these patients died within 1 year (died of disease at 6 and 11 months, respectively). These results suggest that E-cadherin and alpha-catenin undertake important roles as intercellular adhesion molecules; their preserved expression is associated with a better overall survival rate in synovial sarcoma and may have prognostic value. Abnormal levels of beta-catenin, with or without mutation, could contribute to the development and progression of synovial sarcoma, through increasing the proliferative activity of the tumour cells.