Expression of E-cadherin, α-catenin, and β-catenin in tubulolobular carcinoma of the breast

Tubulolobular carcinoma (TLC) of the breast is a rare subtype of breast carcinoma categorized by Fisher et al. (Hum Pathol 8:679–683, 1977) as a tubular variant of lobular carcinoma. E-cadherin is a transmembrane glycoprotein, and complete loss of E-cadherin expression has been observed in invasive lobular carcinoma. Ductal carcinoma retains at least some expression of E-cadherin. Moreover, the adhesive function of E-cadherin is dependent on the integrity of the catenin components, which link E-cadherin to the actin filaments. In order to achieve improved categorization of TLC, we decided to investigate both E-cadherin and the catenins in TLCs and invasive lobular carcinomas. We reviewed all 1,430 cases of primary breast carcinoma that were surgically resected at Saitama Medical Center, Saitama Medical School, and at Saitama Red Cross Hospital between 1990 and 2005. Among these, 16 cases of TLC were reported retrospectively. The results were compared with those of 20 cases of invasive lobular carcinomas that were included as controls. Tumor tissue was immunostained for E-cadherin, α-catenin, and β-catenin. The presence of immunoreactivity in the TLC was seen in 12 (75%) cases for E-cadherin, in 8 (50%) cases for α-catenin, and in 10 (62.5%) cases for β-catenin. However, plasma-membrane-associated staining for E-cadherin, α-catenin, and β-catenin was completely absent in invasive lobular carcinomas. These results suggest the possibility that TLCs are not a variant of lobular carcinoma, but rather ductal carcinomas with a lobular growth pattern.     

Expression and localization of E-cadherin and β-catenin in uterine carcinosarcoma

This study was designed to analyze the subcellular localization of E-cadherin and β-catenin both of which play a critical role in cell–cell adhesion in uterine carcinosarcoma (UCS). We performed an immunohistochemical reaction analysis of the subcellular localization of E-cadherin and β-catenin proteins in 46 cases of UCSs consisting of 28 UCSs with heterologous sarcoma and 18 UCSs with homologous sarcoma and compared their clinicopathological features. In most UCSs, membranous expression of E-cadherin and β-catenin was completely lost in sarcomatous components, but it was preserved in carcinomatous components. Nuclear β-catenin expression was observed significantly more frequently in sarcomatous components (31/46, 67.4%) than in carcinomatous components (22/46, 47.8%; P = 0.0025). In sarcomatous components, nuclear β-catenin expression was found significantly more frequently in heterologous sarcoma (23/28, 82.1%) than in homologous sarcoma (8/18, 44.4%; P = 0.0279). The stage was the only independent prognostic significant factor. These results suggest that reduced membranous expression of E-cadherin and β-catenin may contribute to the biphasic morphology of UCS. Furthermore, although the precise mechanism is unclear, nuclear β-catenin expression in sarcomatous components may also be associated with biphasic morphology and heterologous sarcomatous differentiation.     

KIT, PDGFRα and EGFR analysis in nephroblastoma

Nephroblastoma prognosis has dramatically improved, but an unfavourable prognostic subgroup warrants development of novel therapeutic strategies. Selective KIT, PDGFRalpha and epidermal growth factor receptor (EGFR) tyrosine kinase inhibition evolved as powerful targeted therapy for gastrointestinal stromal tumours and non-small-cell lung cancer. To investigate a potential role for tyrosine kinase inhibition, we analyzed 209 nephroblastomas for immunohistochemical KIT and EGFR expression, 63 nephroblastomas for mutations in KIT exons 9, 11, 13, EGFR exons 18, 19, 20 and 21, and all 209 nephroblastomas for PDGFRalpha exons 12, 14 and 18. Twenty-two tumours (10.5%) expressed KIT, 31 (14.8%) EGFR, and 10 (4.8%) both KIT and EGFR, respectively. KIT expression was relatively more common among high-risk tumours (6/27; 22.3%) compared to low-/intermediate-risk tumours (26/181; 14.4%). Nine patients deceased, four of which had high-risk tumours with KIT expression in two of four and EGFR expression in one of four. There were no KIT, PDGFRalpha or EGFR mutations. Our results suggest no significant contribution of KIT, EGFR or PDGFRalpha mutations to nephroblastoma pathogenesis. Despite a trend towards association of immunohistochemical KIT and EGFR expression with poor outcome in high-risk nephroblastomas, statistical analysis did not yield significant correlations in this subgroup. Therefore, it remains open if KIT, PDGFRalpha or EGFR tyrosine kinase inhibition constitute a therapeutic target in nephroblastoma in the absence of KIT, PDGFRalpha or EGFR mutations.     

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.     

A case of β-Thalassemia with rare gene mutation and the tamily analysis

目的 鉴定1种罕见的β地中海贫血突变类型.方法 血液学分析采用血细胞分析仪及全自动快速电泳分析系统;α珠蛋白常规突变检测采用Gap-PCR;β珠蛋白常规突变检测采用反向点杂交法;样品的基因突变及基因型用β珠蛋白基因全长测序技术确定.结果 先证者具有典型的β地中海贫血临床特点和血液学特性,HbF为5.8％,其父母各项指标均正常.未发现先证者及其家庭成员有已知的α-/β-地中海贫血基因突变,测序发现先证者及其母亲均为CD2 (CAT-CAC)杂合子,父亲为CAC纯合子;先证者有β珠蛋白exon1 CD27 (GCC-GAC)突变,编码的氨基酸由丙氨酸变为天冬氨酸,未发现其父母有CD27突变.结论 CD27 (GCC-GAC)突变是罕见的β珠蛋白基因点突变,有助于指导人群筛查、遗传咨询和临床诊断.     

Immunohistochemical expression of E-cadherin and β-catenin in feline mammary tumours

E-cadherin and β-catenin have been studied in carcinogenesis and tumour progression and reduced membrane expression of these molecules in canine mammary tumours has been associated with a poor prognosis. The present study investigated immunohistochemically the expression of E-cadherin and β-catenin in 53 mammary tumours and 48 hyperplastic or dysplastic lesions from 57 queens. E-cadherin and β-catenin expression was membranous in all samples and there was a significant decrease in expression in malignant tumours and metastases. Cytoplasmic expression of both markers was inversely correlated to the membrane localization. β-catenin nuclear labelling was detected in one lymph node metastasis (60% positive cells) and in the basal/myoepithelial cells of 6/7 ductal tumours. No correlation with survival was found for either marker. These results confirm the role of these proteins in maintaining tissue architecture and in inhibiting cell invasiveness and potentially indicate the oncogenic potential of the Wnt/β-catenin transduction pathway in feline mammary tumours. In addition, specific independent expression of β-catenin in the nuclei of basal/myoepithelial cells might suggest that this molecule is involved in regulation of the mammary stem/pluripotent cell component. Further studies should include more cases of benign mammary neoplasia and further investigate β-catenin nuclear expression in ductal tumours.     

Nuclear β-catenin is increased in systemic sclerosis pulmonary fibrosis and promotes lung fibroblast migration and proliferation

Pulmonary fibrosis is a disease that results in loss of normal lung architecture, but the signaling events that drive tissue destruction are incompletely understood. Wnt/β-catenin signaling is important in normal lung development, but whether abnormal signaling occurs in lung fibrosis due to systemic sclerosis and the consequences of β-catenin signaling toward the fibrogenic phenotype remain poorly defined. In this study, we show nuclear β-catenin accumulation in fibroblastic foci from lungs of patients with systemic sclerosis-associated advanced pulmonary fibrosis. Forced activation of β-catenin signaling in three independently derived sources of normal human lung fibroblasts promotes proliferation and migratory activities but is not sufficient to activate classic markers of fibroblast activation, such as TGF-β, type 1 collagen, α-smooth muscle actin, and connective tissue growth factor. These findings indicate that activation of β-catenin signaling in pulmonary fibroblasts may be a common feature of lung fibrosis, contributing to fibroproliferative and migratory activities associated with the disease.     

Expression of β2 integrins and macrophage-associated antigens in meningeal tumours

This study assessed the expression of leukocyte integrins and macrophage-associated antigens in meningiomas. Fourteen benign meningiomas, ten atypical/anaplastic meningiomas, two hemangiopericytomas and one solitary fibrous tumour (SFT) were included. Frozen sections were immunostained using antibodies directed against leukocyte integrins, CD68, CD14, CD2, CD1a, DRC1 and CD34. Their expression was evaluated semi-quantitatively. Ki67 positive cells were counted. Arachnoid membranes served as controls. Arachnoid cells expressed the β2-integrin subunit and KP1. Beta2 was detected in the tumour cells of 14 meningiomas. In nine cases, this was associated with an α-integrin subunit. There was no statistical difference in the expression of β2 between benign and atypical/anaplastic meningiomas. KP1 was constantly expressed by the tumour cells of meningiomas. It was not expressed by other meningeal tumours. CD34 was detected in the fibrous meningiomas, hemangiopericytomas and the SFT. In each tumour, macrophages were more numerous than T lymphocytes. There was no statistical difference in the density of macrophages and T lymphocytes between the benign and atypical/anaplastic meningiomas. There was no correlation between the Ki67 proliferation index and macrophage infiltration. Meningiomas, through the expression of leukocyte antigens, have a very particular phenotype. The expression of β2 integrins could play a role in the attraction of immunocompetent cells in the stroma of meningiomas. Received: 14 April 1999 / Accepted: 15 July 1999     

A subset of high-grade pulmonary neuroendocrine carcinomas shows up-regulation of matrix metalloproteinase-7 associated with nuclear β-catenin immunoreactivity,independent of EGFR and HER-2 gene amplification or expression

Nuclear translocation of β-catenin has been correlated with epidermal growth factor receptor (EGFR) overexpression/activation in nonsmall cell lung cancer. Less is known on β-catenin transactivation in high-grade pulmonary neuroendocrine tumors and on the status of β-catenin activating EGFR and human epidermal growth factor receptor 2 (HER-2) or β-catenin target genes cyclin D1 and matrix metalloproteinase-7 (MMP-7). β-catenin immunoreactivity was evaluated in 51 large-cell neuroendocrine carcinomas (LCNEC) and 45 small-cell lung carcinomas (SCLC). Nineteen cases were assessed for β-catenin gene exon 3 mutations, expression of MMP-7, and expression/gene amplification of EGFR, HER-2, and cyclin D1. β-catenin was expressed in all 96 high-grade neuroendocrine tumors, the vast majority (94%) showing >50% immunopositive cells. A disarrayed immunoreactivity, however, was commonly encountered consisting in variably altered membrane-associated patterns of staining along with progressive accumulation of cytoplasmic immunoreactivity. In LCNEC, but not in SCLC, the disarrayed patterns correlated with EGFR and HER-2 protein expression. β-catenin nuclear accumulation was found in nine tumors, including seven LCNEC and two SCLC, and was always associated with disarrayed immunoreactivity and increased MMP-7, but not cyclin D1 expression. These cases, however, did not show β-catenin gene mutations or EGFR and HER-2 gene amplification or expression. No association was found between nuclear β-catenin and any clinicopathological variable including patients' survival. The subcellular compartmentalization of β-catenin is profoundly altered in high-grade pulmonary neuroendocrine tumors. A minor subset of these tumors shows β-catenin nuclear accumulation in association with increased expression of MMP-7, but not of cyclin D1, independent of EGFR and HER-2 gene amplification or expression. The authors have no significant financial or other relationship with the manufacturers of any commercial products or commercial services presented in this paper     

Expression of the human β-defensin-1 induced by dehydroandrographolide in human pulmonary gland epithelial cells

In this study we observed the enhanced mRNA and protein expression of human β-defensin-1 (hBD-1) induced by dehydroandrographolide (DA) in human gland epithelial cells and explored the mechanism of DA on infection treatment. Human pulmonary gland epithelial cells were incubated with DA, then were harvested for hBD-1 expression detection. The mRNA expression of hBD-1 was detected by RT-PCR while the protein expression was detected by Western blot. It was found that DA can up-regulate mRNA and protein expression of hBD-1, the optimal concentration was 80 µM, the maximal expression of hBD-1 mRNA and protein occurred after 8 h. The DA can up-regulate mRNA and protein expression of hBD-1 in human gland epithelial cells. It suggests that β-defensin-1 may play an important role in the treatment of infective diseases with DA.     

Detection of β-catenin, gastrokine-2 and embryonic stem cell expressed ras in gastric cancers

ERas activation and GKN2 reduction in gastric cancer has raised some notices in recent years, while nuclear beta-catenin positivity is considered as a tumoral marker. In this study, we compared immunohistochemistry of beta-catenin, GKN2 and ERas on tumoral and non-tumoral mucosae of 50 gastric carcinomas and 13 gastric samples of cancer-free patients. Nuclear positivity of beta-catenin was strong in 31 non-tumoral mucosae (62%) and 29 tumoral mucosae (58%). It was absent in samples of cancer-free patients. There was a correlation between non-tumoral and tumoral zones for nuclear beta-catenin positivity (P=0.013). ERas was positive in 35 non-tumoral tissues (70%) and 31 tumoral tissues (62%) but negatvie in samples of cancer-free patients. It was weak and spotty in non-tumoral mucosae but strong and diffuse in tumors. Positivity of ERas was age-related (P=0.028). However it had background staining effect. GKN2 was expressed in 33 non-tumoral mucosae (66%) and 35 tumoral mucosae (70%). Though GKN2 staining was moderate to strong in non-tumoral tissues and was comparatively weaker in tumors, their difference was minimal and difficult to discern. CONCLUSIONS: Beta-catenin nuclear location could be considered as a paraneoplastic pattern which is considerably tumor-related. ERas may be a potential biomarker for gastric cancer, but advanced studies are wanted. GKN2 reduction is indiscernible by immunostaining.     

Morphological analysis of the trachea and pattern of breathing in βENaC-Tg mice

Cystic fibrosis (CF) is caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene which is a Cl- channel and a regulator of the epithelial Na+ channel (ENaC). We have recently shown that newborn CFTR-deficient mice exhibit abnormalities of the tracheal cartilage leading to altered ventilation (Bonvin et al., 2008). However, the mechanism by which a lack of CFTR causes tracheal cartilage defects remains unknown. The main goal of the present study was to determine whether the development of airway cartilage defects is related to ENac channel dysfunction. We thus performed macroscopic analysis of the trachea and explored ventilatory function in adult βENaC-overexpressing (βENaC-Tg) mice with airway Na+ hyperabsorption and "CF-lung" lung disease, at 2 and 5 month of age. Only minor cartilaginous abnormalities were observed in 8 out of 16 βENaC-Tg mice and in 2 out of 20 littermate controls. Breathing pattern was progressively altered in βENaC-Tg mice as evidenced by a significant decrease in respiratory frequency. Our results suggest that Na+ hyperabsorption alone is not a major contributor to the development of tracheal malformation observed in CF mice and that breathing pattern changes in βENaC-Tg mice likely reflect airflow limitation due to airway mucus obstruction.     

The expression patterns and correlations of chibby, β-catenin, and DNA methyltransferase-1 and their clinicopathological significance in lung cancers

Xu H‐T, Li Q‐C, Dai S‐D, Xie X‐M, Liu D, Wang E‐H. The expression patterns and correlations of chibby, β‐catenin, and DNA methyltransferase‐1 and their clinicopathological significance in lung cancers. APMIS 2011; 119: 750–8. Chibby is an inhibitor of the Wnt pathway. The expression and correlation of chibby in lung cancers is unclear. We considered that the expression pattern of chibby might be related to the expression of β‐catenin and DNA methyltransferase‐1 (DNMT1). We examined the expressions of chibby, β‐catenin, and DNMT1 in 85 lung cancer tissues and corresponding normal lung tissues using immunohistochemistry. The nuclear expression rate of chibby was reduced in lung cancers (p < 0.001). Increased expression of DNMT1 was correlated with the differentiation (p = 0.034) and TNM stage (p = 0.048). The cytoplasmic expression of β‐catenin was correlated with poor differentiation of lung cancers (p = 0.016). The cytoplasmic and membrane expression of chibby was positively correlated with the cytoplasmic (p = 0.025) and membrane (p = 0.029) expressions of β‐catenin. The membrane expression of chibby was negatively correlated with the expression of DNMT1 (p = 0.006). Moreover, the expression of DNMT1 was correlated with the cytoplasmic expression of β‐catenin (p < 0.001). The nuclear expression of chibby is reduced in lung cancers. Chibby may colocalize with β‐catenin. β‐Catenin and DNMT1 may be concurrently expressed and thereby promote the development of lung cancers.