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)

E-cadherin function leads to the density-dependent contact inhibition of cell growth. Because cadherins control the overall state of cell contact, cytoskeletal organization, and the establishment of many other kinds of cell interactions, it remains unknown whether E-cadherin directly transduces growth inhibitory signals. To address this question, we have selectively formed E-cadherin homophilic bonds at the cell surface of isolated epithelial cells by using functionally active recombinant E-cadherin protein attached to microspheres. We find that E-cadherin ligation alone reduces the frequency of cells entering the S phase, demonstrating that E-cadherin ligation directly transduces growth inhibitory signals. E-cadherin binding to beta-catenin is required for cell growth inhibition, but beta-catenin/T-cell factor transcriptional activity is not involved in growth inhibition resulting from homophilic binding. Neither E-cadherin binding to p120-catenin nor beta-catenin binding to alpha-catenin, and thereby the actin cytoskeleton, is required for growth inhibition. E-cadherin ligation also inhibits epidermal growth factor (EGF) receptor-mediated growth signaling by a beta-catenin-dependent mechanism. It does not affect EGF receptor autophosphorylation or activation of ERK, but it inhibits transphosphorylation of Tyr845 and activation of signal transducers and activators of transcription 5. Thus, E-cadherin homophilic binding independent of other cell contacts directly transduces growth inhibition by a beta-catenin-dependent mechanism that inhibits selective signaling functions of growth factor receptors.
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PMID:E-cadherin homophilic ligation inhibits cell growth and epidermal growth factor receptor signaling independently of other cell interactions. 1739 17

SS18-SSX fusion genes resulting from a chromosomal translocation t(X;18)(p11.2;q11.2) are a genetic hallmark of synovial sarcoma. Although such cytogenetic or molecular aberrations have mostly been detected by fluorescence in situ hybridization or reverse transcription-polymerase chain reaction, the expression of SS18-SSX has been poorly investigated at a cellular or tissue level. In this study, biotinylated tyramide (BT)-based in situ hybridization (ISH) was performed to detect SS18-SSX transcripts using formalin-fixed, paraffin-embedded tissues from 15 synovial sarcomas. Digoxigenin-labeled cRNA probes flanking the fusion points of SS18-SSX1 and SS18-SSX2 were generated by in vitro transcription, and hybridized signals were detected by a streptavidin-biotin complex method after chemical enhancement with BT. The localizations of signals were compared with the immunohistochemical expressions of epithelial or neuroectodermal markers and those of cell adhesion including cytokeratins (CAM5.2, AE1/AE3, CK7), epithelial membrane antigen, E-cadherin, beta-catenin, c-erbB-2 (HER2/neu), CD56, and claudin-1. The ISH signals of the SS18-SSX transcripts were identified in 13 synovial sarcomas, and their fusion types correlated with those determined by reverse transcription-polymerase chain reaction. In biphasic tumors, the ISH signals tended to localize to epithelial areas, whereas spindle-cell areas or monophasic fibrous tumors showed a less intense or focal expression pattern. Notably, the expression patterns of AE1/AE3, CK7, and c-erbB-2 often colocalized with the ISH signals (7 of 11 cases positive for each marker). Our results suggest that BT-based ISH can be used as a molecular technique for the detection of SS18-SSX using formalin-fixed, paraffin-embedded tissues.
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PMID:Molecular detection of SS18-SSX fusion gene transcripts by cRNA in situ hybridization in synovial sarcoma using formalin-fixed, paraffin-embedded tumor tissue specimens. 1747 Nov 53

Ovarian carcinomas overexpress endothelin A receptors (ET(A)R) and epidermal growth factor (EGF) receptor (EGFR). In these cells, endothelin-1 (ET-1) triggers mitogenic and invasive signaling pathways that are in part mediated by EGFR transactivation. Combined targeting of ET(A)R, by the specific ET(A)R antagonist ZD4054, and of EGFR by the EGFR inhibitor gefitinib (IRESSA), may offer improvements in ovarian carcinoma treatment. In HEY and OVCA 433 ovarian carcinoma cells, ET-1 or EGF induced rapid activation of EGFR, p42/44 mitogen-activated protein kinase (MAPK), and AKT. ZD4054 was able to reduce the ET-1-induced EGFR transactivation. Gefitinib significantly inhibited EGF- and ET-1-induced EGFR phosphorylation, but incompletely reduced the ET-1-induced activation of downstream targets. ZD4054 plus gefitinib resulted in a greater inhibition of EGFR, MAPK, and AKT phosphorylation, indicating the critical role of these interconnected signaling proteins. ZD4054 effectively inhibited cell proliferation, invasiveness, and vascular endothelial growth factor (VEGF) secretion. Concomitantly, ZD4054 enhanced apoptosis and E-cadherin promoter activity and expression. In both cell lines, the drug combination resulted in a significant decrease in cell proliferation (65%), invasion (52%), and VEGF production (50%), accompanied by a 2-fold increase in apoptosis. The coadministration of ZD4054 enhanced the efficacy of gefitinib leading to partial (82%) or complete tumor regression on HEY ovarian carcinoma xenografts. Antitumor effects were paralleled by biochemical and immunohistologic evidence of decreased vascularization, Ki-67, matrix metalloproteinase-2 (MMP-2), VEGF, MAPK and EGFR, and enhanced E-cadherin expression. The cross-signaling between the EGFR/ET(A)R pathways provides a rationale to combine EGFR inhibitors with ET(A)R antagonists, identifying new effective therapeutic opportunities for ovarian cancer.
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PMID:Combined targeting of endothelin A receptor and epidermal growth factor receptor in ovarian cancer shows enhanced antitumor activity. 1761 94

E-cadherin (E-CD) is an epithelial-specific cell adhesion molecule, whose expression is lost in invasive lobular (ILC) but not in invasive ductal carcinoma (IDC) of the breast. This cell adhesion system can be disrupted by tyrosine kinase c-erbB-2/HER-2/neu. We examined 106 cases of high-grade invasive breast cancer, including 91 IDCs, 12 ILCs and 3 pleomorphic lobular carcinomas (PLCs). We determined Nottingham histological grade and performed immunohistochemistry for estrogen and progesterone receptors (ER/PR), Ki-67, E-CD and c-erbB-2/HER-2/neu with subsequent fluorescence in situ hybridization. Amplification of c-erbB-2/HER-2/neu gene was observed in 55/91 (60.4%) of IDCs, 3/12 (25%) of ILCs and 1/3 (33.3%) of PLCs, and associated with positive axillary lymph nodes. E-CD expression was lost in 14/91 (15.4%) of IDCs, 10/12 (83.3%) of ILCs and 2/3 (66.7%) of PLCs. The loss of E-CD immunoreactivity in IDCs appeared to be associated with c-erbB-2/HER-2/neu gene amplification, negative ER/PR status and positive lymph nodes, whereas E-CD-positive ILCs tended to be HER-2/neu-positive. The biological significance of E-CD expression seems to be different in high-grade IDC and ILC. Oncogenic pathway mediated by c-erbB-2/HER-2/neu may affect the E-CD expression in most invasive ductal breast carcinomas in vivo.
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PMID:Expression of E-cadherin and c-erbB-2/HER-2/neu oncoprotein in high-grade breast cancer. 1782 36

The pathogenesis of polycystic liver disease is not well understood. The putative function of the associated proteins, hepatocystin and Sec63p, do not give insight in their role in cystogenesis and their tissue-wide expression does not fit with the liver-specific phenotype of the disease. We designed this study with the specific aim to dissect whether pathways involved in polycystic kidney diseases are also implicated in polycystic liver disease. Therefore, we immunohistochemically stained cyst tissue specimen with antibodies directed against markers for apoptosis, proliferation, growth receptors, signaling and adhesion. We analyzed genotyped polycystic liver disease cyst tissue (n=21) compared with normal liver tissue (n=13). None of the cysts showed proliferation of epithelial cells. In addition, anti-apoptosis marker Bcl-2 revealed slight increase in expression, with variable increase of apoptosis marker active caspase 3. Growth factor receptors, EGFR and c-erbB-2, were overexpressed and mislocalized. We found EGFR staining in the nuclei of cyst epithelial cells regardless of mutational state of the patient. Further, in hepatocystin-mutant polycystic liver disease patients, apical membranous staining of c-erbB-2 and adhesion markers, MUC1 and CEA, was lost and the proteins appeared to be retained in cytoplasm of cyst epithelia. Finally, we found loss of adhesion molecules E-cadherin and Ep-CAM in cyst epithelium of all patients. Nevertheless, we observed normal beta-catenin expression. Our results show that polycystic liver disease cystogenesis is different from renal cystogenesis. Polycystic liver disease involves overexpression of growth factor receptors and loss of adhesion. In contrast, proliferation or deregulated apoptosis do not seem to be implicated. Moreover differential findings for PRKCSH- and SEC63-associated polycystic liver disease suggest a divergent mechanism for cystogenesis in these two groups.
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PMID:Disrupted cell adhesion but not proliferation mediates cyst formation in polycystic liver disease. 1858 25

Argonaute (Ago) 2 is the catalytic engine of mammalian RNA interference, but little is known concerning the regulation of Ago2 by cell-signaling pathways. In this study we show that expression of Ago2, but not Ago1, Ago3, or Ago4, is elevated in estrogen receptor (ER) alpha-negative (ERalpha(-)) vs. ERalpha-positive (ERalpha+) breast cancer cell lines, and in ERalpha(-) breast tumors. In MCF-7 cells the low level of Ago2 was found to be dependent upon active ERalpha/estrogen signaling. Interestingly, the high expression of Ago2 in ERalpha(-) cells was severely blunted by inhibition of the epidermal growth factor (EGF) receptor/MAPK signaling pathway, using either a pharmacological MAPK kinase inhibitor, U0126, or a small interfering RNA directed against EGF receptor. Half-life studies using cycloheximide indicated that EGF enhanced, whereas U0126 decreased, Ago2 protein stability. Furthermore, a proteosome inhibitor, MG132, blocked Ago2 protein turnover. The functional consequences of elevated Ago2 levels were examined by stable transfection of ERalpha+ MCF-7 cells with full-length and truncated forms of Ago2. The full-length Ago2 transfectants displayed enhanced proliferation, reduced cell-cell adhesion, and increased migratory ability, as shown by proliferation, homotypic aggregation, and wound healing assays, respectively. Overexpression of full-length Ago2, but not truncated forms of Ago2 or an empty vector control, reduced the levels of E-cadherin, beta-catenin, and beta-actin, as well as enhanced endogenous miR-206 activity. These data indicate that Ago2 is regulated at both the transcriptional and posttranslational level, and also implicate Ago2 and enhanced micro-RNA activity in the tumorigenic progression of breast cancer cell lines.
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PMID:Argonaute-2 expression is regulated by epidermal growth factor receptor and mitogen-activated protein kinase signaling and correlates with a transformed phenotype in breast cancer cells. 1878 18

Metastasis is the principal cause of death from breast cancer. ErbB2 (HER-2/neu) has been identified as an important regulator of metastatic potential of breast cancer. The present study investigated the molecular mechanism underlying the role of ErbB2 in malignant phenotypic conversion of MCF10A human breast epithelial cells which originally have 'normal' cell character. Here we report that ErbB2 induces invasion and migration of MCF10A cells though up-regulation of matrix metalloproteinase (MMP)-9. We also observed a marked reduction of an epithelial cell marker, E-cadherin, and an induction of vimentin in ErbB2-MCF10A cells, suggesting that epithelial-mesenchymal transition may play a role in the ErbB2-induced invasion and migration of MCF10A cells. Overexpression of ErbB2 significantly activated p38 MAPK and Akt, while Raf-1/MEK/ERK pathway was not activated by ErbB2. Using pharmacological inhibitors, we further show that p38 MAPK and Akt signaling pathways are crucial for the ErbB2-induced MMP-9 up-regulation, invasion and migration of MCF10A cells. Given that ErbB2 is one of the most important oncogenes in human breast cancer and thus is an attractive therapeutic target, our findings may provide a molecular basis for the promoting role of ErbB2 in breast cancer progression.
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PMID:Overexpression of ErbB2 induces invasion of MCF10A human breast epithelial cells via MMP-9. 1902 65

Tyrosine phosphorylation of beta-catenin, an intracytoplasmic cadherin-binding protein, causes disruption of the cadherin-mediated cell adhesion system in cancer cells. We identified that the c-erbB-2 protein activated by TGFalpha was capable of binding to the 12th armadillo repeat (arm12) of beta-catenin with increased phosphorylation-state level. We produced a monoclonal antibody, 4G7, which recognizes a phosphorylated-tyrosine residue (Tyr-654) located at arm12 of beta-catenin. Tyrosine phosphorylation of the arm12 was detected after stimulation with TGFalpha in TMK-1. Immunoprecipitation analyses using 4G7, anti-beta-catenin, alpha-catenin, the c-erbB-2 gene product and phosphotyrosine antibodies indicated that tyrosine phosphorylation of the arm12 was closely correlated with dissociation between E-cadherin/beta-catenin and alpha-catenin or the c-erbB-2 gene product, but not with dissociation between beta-catenin and E-cadherin. Immunocytochemical staining of TMK-1 cells using the 4G7 antibody revealed that tyrosine phosphorylation of the arm12 was localized at cell-cell contact sites of cancer cells transiently and only after TGFalpha treatment. Immunohistochemical localization of the 4G7 antibody was observed in cancer cells at the invasive front where they detached from cancer nests. These findings indicated that the tyrosine phosphorylation of arm12 is a key marker of cadherin dysfunction and the 4G7 antibody may be useful in screening for a beta-catenin phosphorylation ligand or tyrosine kinases.
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PMID:Tyrosine-phosphorylation of the 12th armadillo-repeat of beta-catenin is associated with cadherin dysfunction in human cancer. 1963 72

In ovarian cancer, it has been shown that E-cadherin is down-regulated by epidermal growth factor (EGF) receptor (EGFR) activation, and that cells with low E-cadherin expression are particularly invasive. Although it is generally believed that reactive oxygen species play important roles in intracellular signal transduction, the role of reactive oxygen species in EGF-mediated reductions in E-cadherin remains to be elucidated. In this study, we show that EGF treatment down-regulated E-cadherin by up-regulating its transcriptional repressors, Snail and Slug, in human ovarian cancer cells. Using 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate acetyl ester staining, we found that intracellular hydrogen peroxide (H(2)O(2)) production was increased in EGF-treated cells and could be inhibited by treatment with an EGFR inhibitor, AG1478, or an H(2)O(2) scavenger, polyethylene glycol (PEG)-catalase. In addition, PEG-catalase diminished EGF-induced p38 MAPK, but not ERK1/2 or c-Jun N-terminal kinase, phosphorylation. PEG-catalase and the p38 MAPK inhibitor SB203580 abolished EGF-induced Snail, but not Slug, expression and E-cadherin down-regulation. Furthermore, the involvement of p38 MAPK in the down-regulation of E-cadherin was confirmed using specific p38alpha MAPK small interfering RNA. Finally, we also show that EGF-induced cell invasion was abolished by treatment with PEG-catalase and SB203580, as well as p38alpha MAPK small interfering RNA, and that forced expression of E-cadherin diminished intrinsic invasiveness as well as EGF-induced cell invasion. This study demonstrates a novel mechanism in which EGF down-regulates E-cadherin expression through production of H(2)O(2), activation of p38 MAPK, and up-regulation of Snail in human ovarian cancer cells.
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PMID:Hydrogen peroxide mediates EGF-induced down-regulation of E-cadherin expression via p38 MAPK and snail in human ovarian cancer cells. 2061 May 39

Expression of E-cadherin, alpha-, beta- and gamma-catenins were studied in 100 patients with primary breast cancer compiled of 57 invasive ductal carcinomas (IDC) and 43 invasive lobular carcinomas (ILC) by means of immunohistochemistry. Loss of E-cadherin was observed in 26 (45.6%), and alpha-, beta- and gamma-catenin expression was lacking in 22 (38.6%), 27 (47.4%) and 22 (38.6%) IDCs, respectively. The expression in ILCs was significantly lower, as compared to IDCs (p<0.001). Immunostaining of both E-cadherin and catenins was completely lacking in 27 (47.4%) IDCs and 30 (93.8%) ILCs. Go-expression of E-cadherin/beta-catenin or E-cadherin/gamma-catenin was preserved more frequently than that of E-cadherin/alpha-catenin complexes. E-cadherin/catenin complex expression showed significant positive correlation with histological differentiation (p=0.037), ER (p=0.017) and PR expression (p=0.052), and negative correlation with c-erbB-2 receptor overexpression (p=0.046). Patients with tumours showing adhesion complexes containing alpha-catenin had an increased overall survival rate compared to other patients. Expression of either E-cadherin or alpha-catenin only, without the formation of entire adhesion complexes, was not correlated with overall survival. Thus, determination of both E-cadherin and catenins is suggested to add further information to estimate the prognosis of breast cancer patients.
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PMID:Expression of E-cadherin/catenin complexes in breast cancer. 2152 42


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