Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell-cell adhesion determines the polarity of cells and participates in the maintenance of the cell societies called tissues. Cell-cell adhesiveness is generally reduced in human cancers. Reduced intercellular adhesiveness allows cancer cells to disobey the social order, resulting in destruction of histological structure, which is the morphological hallmark of malignant tumors. Reduced intercellular adhesiveness is also indispensable for cancer invasion and metastasis. A tumor-suppressor gene product, E-cadherin, and its undercoat proteins, catenins, which connect cadherins to actin filaments, are located at lateral borders, concentrating on adherens junctions, of epithelial cells and establish firm cell-cell adhesion. The E-cadherin cell adhesion system in cancer cells is inactivated by various mechanisms that reflect the morphological and biological characteristics of the tumor. Silencing of the E-cadherin gene by DNA hypermethylation around the promoter region occurs frequently, even in precancerous conditions. In diffuse infiltrating cancers, mutations are found in the genes for E-cadherin and alpha- and beta-catenins. At the invading front of cancers, the E-cadherin cell adhesion system is inactivated by tyrosine phosphorylation of beta-catenin; an oncogene product, c-erbB-2 protein, is found to associate directly with beta-catenin. The E-cadherin cell adhesion system cross-talks with the Wingless/Wnt signaling pathway through beta-catenin, and expression of genes, which participate in cancer morphogenesis, may be regulated in conjunction with the Wingless/Wnt signaling pathway. Dysadherin, a newly identified cancer-associated cell membrane glycoprotein, down-regulates E-cadherin and promotes cancer metastasis. In conclusion, inactivation of the E-cadherin cell adhesion system by both genetic and epigenetic mechanisms plays a significant role during multistage human carcinogenesis.
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PMID:Cell adhesion system and human cancer morphogenesis. 1284 64

Trophoblast differentiation is a key event in human placental development. During extravillous trophoblast (EVT) differentiation, stem cells from the anchoring villi detach from their basement membrane and proliferate to form aggregates called trophoblast cell columns (TCCs). They subsequently invade the decidua and differentiate into interstitial and endovascular trophoblasts. The influence of the decidua on EVT differentiation is controversial. We therefore compared the pattern of trophoblast differentiation marker expression in viable intrauterine and tubal pregnancies, as decidual cell markers (prolactin [PRL] and insulin-like growth factor binding Protein-1 [IGFBP1]) were only expressed in endometrial implantation sites. Extravillous trophoblast differentiation in anchoring villi from uterine and ectopic pregnancies exhibited a comparable phenotypical switch: alpha6 integrin subunit, E-cadherin, EGF receptor, Ki 67 and connexin 40 were localized in the proximal part of the TCC, while alpha5beta1 and alpha1 integrins, c-erb B2, hPL and HLA-G were expressed by invasive cytotrophoblasts. The cyclin-dependent kinase inhibitors p16 and p57 were mainly detected in invasive cytotrophoblasts some distance from the columns. However, the TCC was markedly longer in tubal pregnancy than in intrauterine pregnancy. These findings suggest that the decidua is not necessary to trigger EVT invasion, but that it is likely to limit the extent of the TCC and to accelerate the onset of EVT migration.
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PMID:Evidence of a limited contribution of feto-maternal interactions to trophoblast differentiation along the invasive pathway. 1288 91

Tight junctions (TJs) are the most apical cell-cell junctions, and claudins, the recently identified TJ proteins, are critical for maintaining cell-cell adhesion in epithelial cell sheets. Based on their in vivo distribution and the results of overexpression studies, certain claudins, including claudin-1 and -4, are postulated to increase, whereas other claudins, especially claudin-2, are postulated to decrease the overall transcellular resistance. The overall ratio among claudins expressed in a cell/tissue has been hypothesized to define the complexity of TJs. Disruption of the TJs contributes to various human diseases, and a correlation between reduction of TJ function and tumor dedifferentiation has been postulated. The epidermal growth factor (EGF) receptor (EGFR) is overexpressed in a wide spectrum of epithelial cancers, and its expression correlates with a more metastatic cancer phenotype. However, normal functioning of EGFR is essential for normal epithelial cell proliferation and differentiation. The role of EGFR-dependent signaling in the development and maintenance of epithelial TJ integrity has not been studied in detail. This study demonstrates that, in polarized Madin-Darby canine kidney II cells, EGF-induced EGFR activation significantly inhibited claudin-2 expression while simultaneously inducing cellular redistribution and increased expression of claudin-1, -3, and -4. Accompanying these EGF-induced changes in claudin expression was a 3-fold increase in transepithelial resistance, a functional measure of TJs. In contrast, there were no alterations in protein expression and/or intracellular localization of other TJ-related proteins (ZO-1 and occludin) or adherens junction-associated proteins (E-cadherin and beta-catenin), suggesting that EGF regulates TJ function through selective and differential regulation of claudins.
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PMID:Epidermal growth factor receptor activation differentially regulates claudin expression and enhances transepithelial resistance in Madin-Darby canine kidney cells. 1459 19

Human papillomavirus (HPV) type 16 is causally associated with a subset of oral cancers, predominantly those cancers arising in the oropharynx (OP). Increased HPV16 E6 and E7 oncogene expressions are responsible for the malignant transmission in these cancers. ErbB-2 is the family member most closely implicated in human cancer, where it is overexpressed in about 30% of carcinomas including head and neck squamous cell carcinoma. Coexpressions of E6/E7 and ErbB-2 downregulate E-cadherin and catenin expression, therefore induces metastatic process. Trastuzumab is a humanized monoclonal antibody that recognizes the ErbB-2 protein receptor and breakthrough in the treatment of metastatic breast cancer in combination with chemotherapeutic agents. This antibody is also in clinical testing for adjuvant treatment of breast cancer. We propose that trastuzumab as an adjuvant treatment may decrease process of tumor metastasis in oropharyngeal cancer patients who completed primary treatment (surgery and/or radiotherapy) and show expression of both HPV16 E6/E7 and erbB-2 oncoproteins. In vitro and in vivo studies with trastuzumab in these subgroup of patients may support our hypothesis.
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PMID:Adjuvant targeted therapy with trastuzumab may decrease metastatic capacity in specific group of oropharyngeal cancer patients: downregulation of E-cadherin-catenin complex by cooperative effect of erbB-2 and human papillomavirus type 16 E6/E7 protooncogenes. 1523 90

E-Cadherin regulates epithelial cell adhesion and is critical for the maintenance of tissue integrity. In sporadic diffuse-type gastric carcinoma, mutations of the E-cadherin gene are frequently observed that predominantly affect putative calcium binding motifs located in the linker region between the second and third extracellular domains. A single amino acid change (D370A) as found in a gastric carcinoma patient reduces cell adhesion and up-regulates cell motility. To study the effect of this mutation on the dynamics of cell adhesion and motility in living cells, enhanced green fluorescent protein (EGFP) was C-terminally fused to E-cadherin. The resulting mutant E-cadherin-EGFP fusion protein with a point mutation in exon 8 (p8-EcadEGFP) and a wild-type E-cadherin-EGFP fusion construct (wt-EcadEGFP) were expressed in human MDA-MB-435S cells. Fluorescent images were acquired by time-lapse laser scanning microscopy and E-cadherin was visualized during contact formation and in moving cells. Spatial and temporal localization of p8- and wt-EcadEGFP differed significantly. While wt-EcadEGFP was mainly localized at lateral membranes of contacting cells and formed E-cadherin puncta and plaques, p8-EcadEGFP-expressing cells frequently formed transient cell-cell contacts. During random cell migration, p8-EcadEGFP was found in lamellipodia. In contrast, wt-EcadEGFP localized at lateral cell-cell contact sites in low or non-motile cells. Inhibition of the epidermal growth factor (EGF) receptor, which plays a major role in lamellipodia formation and cell migration, reduced the motility of p8-EcadEGFP-expressing cells and caused lateral membrane staining of p8-EcadEGFP. Conversely, EGF induced cell motility and caused formation of lamellipodia that were E-cadherin positive. In conclusion, our data show that mutant E-cadherin significantly alters the dynamics of cell adhesion and motility in living cells and interferes with the formation of stable cell-cell contacts.
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PMID:Dynamics of cell adhesion and motility in living cells is altered by a single amino acid change in E-cadherin fused to enhanced green fluorescent protein. 1525 55

Recent studies on gene molecular profiling using cDNA microarray in a relatively small series of breast cancer have identified biologically distinct groups with apparent clinical and prognostic relevance. The validation of such new taxonomies should be confirmed on larger series of cases prior to acceptance in clinical practice. The development of tissue microarray (TMA) technology provides methodology for high-throughput concomitant analyses of multiple proteins on large numbers of archival tumour samples. In our study, we have used immunohistochemistry techniques applied to TMA preparations of 1,076 cases of invasive breast cancer to study the combined protein expression profiles of a large panel of well-characterized commercially available biomarkers related to epithelial cell lineage, differentiation, hormone and growth factor receptors and gene products known to be altered in some forms of breast cancer. Using hierarchical clustering methodology, 5 groups with distinct patterns of protein expression were identified. A sixth group of only 4 cases was also identified but deemed too small for further detailed assessment. Further analysis of these clusters was performed using multiple layer perceptron (MLP)-artificial neural network (ANN) with a back propagation algorithm to identify key biomarkers driving the membership of each group. We have identified 2 large groups by their expression of luminal epithelial cell phenotypic characteristics, hormone receptors positivity, absence of basal epithelial phenotype characteristics and lack of c-erbB-2 protein overexpression. Two additional groups were characterized by high c-erbB-2 positivity and negative or weak hormone receptors expression but showed differences in MUC1 and E-cadherin expression. The final group was characterized by strong basal epithelial characteristics, p53 positivity, absent hormone receptors and weak to low luminal epithelial cytokeratin expression. In addition, we have identified significant differences between clusters identified in this series with respect to established prognostic factors including tumour grade, size and histologic tumour type as well as differences in patient outcomes. The different protein expression profiles identified in our study confirm the biologic heterogeneity of breast cancer and demonstrate the clinical relevance of classification in this manner. These observations could form the basis of revision of existing traditional classification systems for breast cancer.
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PMID:High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses. 1581 18

The established method in prognosis of breast cancer includes detection of molecular markers, such as the estrogen receptor (ER), progesterone receptor (PR), and HER-2/neu. These markers are routinely checked via immunohistochemistry (IHC). HER-2/neu is also detected by fluorescent in situ hybridization (FISH). Flow cytometric analysis has not yet been used for detection of such markers. Flow cytometry was performed on four established breast cancer cell lines: MCF7, T47D, BT474, MDA-MB-231, and on one normal breast epithelial cell line: MCF10A. Flow cytometric analysis was used for the detection of ER, PR, HER-2/neu, epidermal growth factor receptor (EGFR), and E-cadherin. Currently, EGFR and E-cadherin are not standard predictive factors in determining survival of breast cancer patients, but both may be beneficial to prognosis. Cells undergoing flow cytometric analysis lost marker expression with increasing passage number. The highest expression was found at cells passaged 0-1 times. MCF7, T47D, and BT474 all had similar marker expression patterns. E-cadherin demonstrated a strongly positive pattern with marker expression of 85-92% among the three cell lines. ER, PR, and HER-2/neu demonstrated a weakly positive expression pattern when compared with E-cadherin. Marker expression ranged from 15 to 61%. These three cell lines were almost negative for expression of EGFR where expression ranged from 0 to 6%. MDA-MB-231 had almost no expression of all 5 markers, with positive values ranging from 0 to 5%. MCF10A had weak positive to almost negative expression values of ER, PR, HER-2/neu, and E-cadherin, which ranged from 3 to 13%. EGFR, both surface and cytoplasmic markers, again were not expressed in MCF10A cells with an expression value of <1%. We found that ER, PR, and HER-2/neu marker expressions in 5 out of 5 cell lines were consistent with established expression patterns. EGFR and E-cadherin expression in 4 out of 5 cell lines were also consistent with established expression patterns. We have shown that flow cytometry provides quantitative data on expression patterns of important prognostic markers in breast cancer.
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PMID:Flow cytometry: a new approach for the molecular profiling of breast cancer. 1627 61

Apoptosis and epithelial-mesenchymal transdifferentiation (EMT) occur in stressed tubular epithelial cells and contribute to renal fibrosis. Transforming growth factor (TGF)-beta(1) promotes these responses and we examined whether the processes were interdependent in vitro. Direct (caspase inhibition) and indirect [epidermal growth factor (EGF) receptor stimulation] strategies were used to block apoptosis during TGF-beta(1) stimulation, and the subsequent effect on EMT was assessed. HK-2 cells were exposed to TGF-beta(1) with or without preincubation with ZVAD-FMK (pan-caspase inhibitor) or concomitant treatment with EGF plus or minus preincubation with LY-294002 (PI3-kinase inhibitor). Cells were then assessed for apoptosis and proliferation by flow cytometry, crystal violet assay, and Western blotting. Markers of EMT were assessed by microscopy, immunofluorescence, real-time RT-PCR, Western blotting, PAI-1 reporter assay, and collagen gel contraction assay. TGF-beta(1) caused apoptosis and priming for staurosporine-induced apoptosis. This was blocked by ZVAD-FMK. However, ZVAD-FMK did not prevent EMT following TGF-beta(1) treatment. EGF inhibited apoptosis and facilitated TGF-beta(1) induction of EMT by increasing proliferation and accentuating E-cadherin loss. Additionally, EGF significantly enhanced TGF-beta(1)-induced collagen I gel contraction. EGF increased Akt phosphorylation during EMT, and the prosurvival effect of this was confirmed using LY-294002, which reduced EGF-induced Akt phosphorylation and reversed its antiapoptotic and proproliferatory effects. TGF-beta(1) induces EMT independently of its proapoptotic effects. TGF-beta(1) and EGF together lead to EMT. EGF increases proliferation and resistance to apoptosis during EMT in a PI3-K Akt-dependent manner. In vivo, EGF receptor activation may assist in the selective survival of a transdifferentiated, profibrotic cell type.
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PMID:TGF-beta1-induced EMT can occur independently of its proapoptotic effects and is aided by EGF receptor activation. 1636 39

Overexpression of the epidermal growth factor (EGF) receptor occurs frequently in ovarian cancer and is associated with poor patient prognosis. A constitutively active mutant EGF receptor termed variant III (EGFRvIII) has been detected at a high frequency in many human tumors, including those of the ovary. To identify the consequences of EGFRvIII expression in ovarian tumor cells, we introduced EGFRvIII into the epithelial ovarian cancer cell line (OVCA 433). The EGFRvIII-transfected cells displayed a dissociated, motile phenotype and fibroblastic morphology. The EGFRvIII-dependent phenotype was comparable to that observed in EGF-stimulated parental OVCA 433 cultures and required the catalytic activity of the mutant receptor. Disruption of adherens and desmosomal junctions in EGFRvIII expressing cells was evident by immunofluorescent detection of specific junctional components. In addition, Western blot analysis confirmed decreased levels of cellular plakoglobin and beta-catenin in EGFRvIII-expressing cells, and E-cadherin protein and mRNA were nearly absent. The loss of E-cadherin was accompanied by decreased expression of additional ovarian epithelial markers, including keratins 7, 8, and 18 and mucins 1 and 4. In contrast, the mesenchymal markers N-cadherin and vimentin were elevated in EGFRvIII expressing cells. Overall, the switch in cadherins from E-cadherin to N-cadherin, coupled with gain of vimentin expression and loss of the epithelial keratins and mucins typically expressed in well-differentiated epithelial ovarian carcinomas, are consistent with transition to a mesenchymal phenotype as an outcome of EGFRvIII expression. These findings suggest that EGFRvIII expression may regulate phenotypic plasticity in ovarian cancer and thereby contribute to more aggressive disease.
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PMID:Mesenchymal transformation in epithelial ovarian tumor cells expressing epidermal growth factor receptor variant III. 1678 82

We present a case of an unusual tumor that occurred in the perianal area of a 64-year-old woman. Clinical investigation revealed no tumor elsewhere. The lesion was removed and the patient is alive without signs of metastasis or recurrence 5.5 years after surgery. Histopathologically, the neoplasm was composed of single-cell cords of uniform round to ovoid cells intermixed with round to elongated tubules showing decapitation secretion at the luminal border. The tubules were mainly composed of a single cell layer, but focally multilayered epithelium (without evidence of myoepithelial cell differentiation) was seen as well as discrete cribriform structures and intraluminal bridges. Overall, the cell cord component slightly dominated over the tubular component, and the two were intermixed. A vague targetoid arrangement of the cell cords was seen focally. Immunohistochemically, the tumor cells in both components reacted positively for E-cadherin, 34betaE12, estrogen receptors and progesterone receptor and were negative for HER2/neu (c-erbB-2). There was no evidence of myoepithelial cell differentiation with calponin. We believe that the present case is best classified as mammary type tubulolobular carcinoma and, given the location, the origin in anogenital mammary-like glands most likely.
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PMID:Mammary type tubulolobular carcinoma of the anogenital area: report of a case of a unique tumor presumably originating in anogenital mammarylike glands. 1693 66


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