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)

Pulmonary epithelial cells are important in lung growth, development, and injury. H441 pulmonary adenocarcinoma cells may be a useful model for studying pulmonary epithelial cell growth factor responses in vitro. Isolated pulmonary epithelial type II cells proliferate in response to transforming growth factor (TGF)-alpha via the epidermal growth factor (EGF) receptor. Type II cells also proliferate in response to hepatocyte growth factor (HGF). In the present study, H441 cell responses to these growth factors were examined, and compared to type II cells. Both the EGF-R and the c-met proto-oncogene receptor, to which HGF binds, were immunoprecipitated from H441 cells. In H441 cells, addition of TGF-alpha resulted in phosphorylation of the EGF receptor and increased cell number and tritiated thymidine incorporation. Incubation with HGF resulted in phosphorylation of its c-met proto-oncogene receptor in type II and H441 cells, and also increased cell number and tritiated thymidine incorporation. Both HGF and TGF-alpha stimulated phosphorylation of the intracellular signaling molecules p42 and p44 mitogen activated protein kinases in H441 cells. H441 cells exhibited responses to mitogenic growth factors similar to type II cells and may be useful as a model for type II cell growth factor responses and signal transduction.
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PMID:H441 pulmonary epithelial cell mitogenic effects and signaling pathways in response to HGF and TGF-alpha. 945 67

MDA-MB-468 is a human mammary adenocarcinoma cell line that overexpresses the epidermal growth factor (EGF) receptor and undergoes programmed cell death (apoptosis) in response to EGF treatment. Programmed cell death was shown to be greatly enhanced when cells were growth-arrested prior to EGF treatment. Apoptosis was characterized by an initial rounding up and detachment of the cells from their substrate starting about 12 h after EGF treatment, followed by chromatin condensation, nuclear fragmentation and oligonucleosomal fragmentation of the DNA at about 24 to 48 h. Cell death was dependent on de novo protein synthesis. We found a rapid induction of c-fos, c-jun and junB at the mRNA level after about 30 min of EGF treatment and a more delayed upregulation of fosB and fra-1. The junD gene was expressed in the absence of EGF, and it was moderately induced within 30 min of growth factor addition. The increase of the different fos and jun mRNAs were paralleled by an increase of activator protein-1 (AP-1) DNA binding activity. A characterization of the AP-1 complex revealed similar levels of several Fos and Jun proteins. Based on the kinetics of AP-1 accumulation and cell death, it seems likely that AP-1 contributes to the apoptotic cell death of EGF receptor-overexpressing MDA-MB-486 cells.
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PMID:EGF-induced programmed cell death of human mammary carcinoma MDA-MB-468 cells is preceded by activation AP-1. 953 53

Barrett's esophagus, or specialized intestinal metaplasia, is a common condition associated with gastroesophageal reflux and an increased risk for adenocarcinoma of the esophagus and gastric cardia. Currently, clinical surveillance for early detection of adenocarcinoma relies on the histopathological assessment of dysplasia. In this review we present data from the published literature, and combine this with results from our own research, to address what is currently known about the environmental factors and the molecular changes thought to be important in the pathogenesis of Barrett's esophagus. The most important and well-characterized molecular changes, preceding the development of dysplasia, are alterations in the p53 and erbB-2 genes and aneuploidy. These molecular changes, as well as environmental influences, such as the quality and quantity of gastroduodenal refluxate, may result in abnormal cell proliferation which in turn promotes further genetic abnormalities and deregulation of cell growth. The identification of molecular changes, in the context of predisposing environmental factors, will enhance our understanding of the malignant progression of Barrett's esophagus leading to more effective surveillance and treatment.
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PMID:Recent developments in the molecular characterization of Barrett's esophagus. 957 72

New therapeutic strategies are now being developed against adenocarcinoma associated with erbB-2 amplification, particularly by inhibiting p185erbB-2 expression. Antisense oligodeoxynucleotides seem promising for this purpose as long as they are efficiently protected against degradation and targeted into the cells. We present antisense oligonucleotide carriers, the supramolecular biovectors (SMBVs), for which we have already demonstrated the ability to improve both cellular uptake and protection of oligodeoxynucleotide. The present work demonstrates that SMBVs elicit a specific and non-toxic action of antisense compounds in a cell model, irrespective of their sensitivity to nucleases. This is a major point, considering the specificity problems associated with the use of nuclease-resistant phosphorothioate oligodeoxynucleotide. SMBVs improve antisense efficiency of oligodeoxynucleotide designed against p185erbB-2, with a complete growth arrest of SK-Br-3, human adenocarcinoma mammary cells that overexpress p185erbB-2 and no effect on MCF-7 cells that normally express p185erbB-2. The comparison of SMBVs with DOTAP reveals the statistically higher efficiency of SMBVs, which allows the antisense inhibition of p185erbB-2 expression in 65-75% of SK-Br-3 cells (P < 0.05). The efficiency and controlled synthesis of SMBVs underline their potentialities as oligodeoxynucleotide carriers for in vivo experiments.
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PMID:SupraMolecular BioVectors (SMBV) improve antisense inhibition of erbB-2 expression. 965 60

Molecular assays related to cell proliferation correlate with stage and/or survival in a variety of tumors. We immunostained formalin-fixed, paraffin-embedded tissue sections from 61 patients with gastric adenocarcinoma (21 biopsy and 40 gastrectomy specimens) for cyclin A, cyclin B1, p34cdc2, p120, MIB1, and proliferating cell nuclear antigen (PCNA) by automated methods. HER-2/neu gene amplification was analyzed by automated fluorescence in situ hybridization (FISH). Immununostains, FISH results, and pathologic stage were compared with length of survival. Forty-three percent of the cases showed amplification of HER-2/neu. Sixty-two percent of cases showed positive immunostaining for cyclin A, 38% for cyclin B1, 31% for p34cdc2, 49% for p120, 69% for MIB1, and 33% for PCNA. On univariate analysis, pathologic stage (P = .003) and HER-2/neu gene amplification (P < .001) correlated with length of survival. Cyclin A, cyclin B1, p34cdc2, p120, MIB1, and PCNA did not correlate with survival. On multivariate analysis, pathologic stage (P = .015) and HER-2/neu gene amplification (P = .002) independently predicted survival. These correlations were unrelated to tubular or signet ring cell histologic characteristics or to location within the cardia or more distally. Pathologic stage and HER-2/neu gene amplification by FISH were independent prognostic factors in gastric cancer, but the various proliferation markers that we studied did not correlate with survival.
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PMID:Prognostic factors in gastric cancer. 975 67

Limited information is currently available on chromosomal abnormalities in esophageal adenocarcinoma and associated premalignant lesions. In this study, numeric changes affecting chromosomes 4, 6, 7, 8, 9, 10, 11, 12, 17, 18, X, and Y were analyzed by using fluorescence in situ hybridization (FISH) with chromosome-specific centromere DNA probes in 12 esophageal adenocarcinomas. In addition, TP53 overexpression, measured by immunohistochemistry, and amplification of HER-2/neu and C-MYC, detected by FISH, were analyzed within the same tumors. The most common numeric abnormalities detected were gains of chromosomes 12 (8 cases), 6 (7 cases), 7 (7 cases), and 11 (6 cases). The total number of abnormal chromosomes varied from 0 to 10, with an average of 4.6 per case. Overexpression of TP53 was present in 9 of 12 cases. No correlation was noted between the degree of aneusomy and TP53 overexpression. In contrast, HER-2/neu amplification was present in two cases, both with large numbers of aneusomic chromosomes. Amplification of C-MYC was detected in only one case that had a moderate number of numeric abnormalities. In a subset of cases in which premalignant lesions were examined, aneusomy was found to be an early change, frequently present in both Barrett's esophagus and dysplastic regions. In contrast, gene amplification and TP53 overexpression were restricted to more advanced areas of dysplasia and malignancy. Screening larger cohorts of patients with Barrett's esophagus or dysplasia for numeric abnormalities of chromosomes 6, 7, 11, and 12 may determine whether any of these abnormalities are predictive markers of progression to malignancy.
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PMID:Interphase cytogenetics of esophageal adenocarcinoma and precursor lesions. 977 3

Adenocarcinoma of the pancreas carries a grave prognosis for affected patients. Certain oncogenes (K-ras and HER-2/neu) are mutated in a large proportion of these aggressive tumors. Adenocarcinoma of the pancreas has also been associated with loss of tumor suppressor genes (p53, DPC4, p16/MTS), either by deletion or by mutation and loss of function. Growth factors (EGF, TGF-alpha, HGF) and growth factor receptors (EGF-R, c-met, CCK) are expressed at levels not found in the normal pancreas. Finally, factors important for angiogenesis (FGF, integrins, selectins) are likely to play an important role in the growth and metastasis of clinically relevant tumors. This review attempts to summarize and assimilate current research into the molecular and cellular biology of pancreatic cancer.
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PMID:The molecular and cellular biology of pancreatic cancer. 980 1

Bax and Bcl-2 are proteins that regulate programmed cell death and apoptosis. The expression of these proteins can be regulated, at least in part, by the tumor suppressor p53, but the effects of p53 are highly tissue specific. In an effort to better understand the relation between p53 and the in vivo control of the expression of Bax and Bcl-2 in adenocarcinomas of the breast, we evaluated by immunohistochemistry the expression of Bcl-2 and Bax in 149 invasive ductal carcinomas, 135 of which were chosen because of their p53 immunopositivity. The percentages of Bcl-2-immunopositive tumor cells were significantly lower in the p53-positive (median 20%) subsets as compared to the p53-negative (median 85%) subsets (P = 0. 004). Comparisons of the percentages of p53-immunopositive tumor cells with the percentages of Bcl-2- and Bax-positive cells (as continuous variables) revealed a significant inverse correlation between Bcl-2 and p53 (r = -0.41, P < 0.001) but not between Bax and p53. In the p53-positive subset, the percentages of Bax- and Bcl-2-immunopositive tumor cells were correlated positively (r = 0. 27, P = 0.002), suggesting that the expression of these genes may be co-regulated to some extent in these breast cancers. Higher percentages of Bcl-2-positive tumor cells were also associated with estrogen receptor positivity (P = 0.03), low histological tumor grade (P = 0.03), and low T stage (P = 0.02), whereas Bax immunostaining was associated only with c-erbB-2 immunopositivity (P = 0.02). Although the number of cases was small and treatment was non-uniform, preliminary correlations with clinical outcome data suggest that the prognostic significance of Bcl-2 may be enhanced by inclusion of Bax data in patients with p53-immunopositive adenocarcinoma of the breast, at least for patients with node-negative disease. Taken together, these data suggest that, despite the ability of p53 to bind directly to the Bax gene promoter, the regulation of Bax in human breast cancers does not necessarily correlate with p53 status, implying that regulation of this pro-apoptotic gene in these tumors is complex and probably influenced by several factors.
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PMID:Analysis of Bax and Bcl-2 expression in p53-immunopositive breast cancers. 1004 37

Historical information and pathological material from 150 consecutive patients with localized adenocarcinoma of the lung was collected to evaluate oncogene expression of erbB-2 and p53, and erbB-2 gene amplification. Pathological material after resection was reviewed to verify histological staging, and patient follow-up was complete in all cases for at least 68 months. Immunohistochemistry of erbB-2 (HER-2/neu) and p53 oncogene expression was performed on two separate paraffin tumor blocks for each patient with normal lung as control. Gene amplification of erbB-2 was measured after DNA extraction from 20-micrometer sections of erbB-2-positive and -negative tumors. All analyses were blinded and included Kaplan-Meier survival estimates with Cox proportional hazards regression modeling. Two adequate blocks of tumor and normal lung were available for 138 (92%) patients. Immunohistochemical identification of expression of p53 was observed in 49 (37%) patients and erbB-2 in 17 (13%) patients. DNA dot blot analyses were performed on 17 erbB-2-positive and 13 randomly selected erbB-2-negative tumors. There was 1 (6%) of 17 erbB-2-positve tumors with 4-fold erbB-2 gene amplification. Actual 5-year survival was 63% and actuarial 10-year survival was 59% for the entire population of 150 patients. Significant univariate predictors (P < 0.05) of cancer death were the presence of symptoms, tumor size >3 cm, poor differentiation, visceral pleural invasion, and p53 expression. Multivariate analysis associated symptoms and p53 expression as independent factors with decreased survival. Thus, this project examined p53 and erbB-2 expression in patients with localized adenocarcinoma and associated p53 status with survival. Multicenter collection of data should allow the development of a model of cancer recurrence in this most common lung cancer.
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PMID:Localized adenocarcinoma of the lung: oncogene expression of erbB-2 and p53 in 150 patients. 981 29

The recombinant oncotoxin OLX-209 [e23(Fv)PE38KDEL] has been developed to target cancers with erbB-2 expression and is nearing a clinical trial. Important in clinical planning is the selection of patients on the basis of tumor expression of erbB-2. ErbB-2 gene amplification occurs in cancers of the breast, stomach, and ovary. Patients with these diseases and evident overexpression are candidates for OLX-209 therapy. In lung cancer, overexpression of erbB-2 is also frequent, but in most cases, it is not caused by gene amplification. This study demonstrates that OLX-209 has activity on lung cancer cells with varying levels of erbB-2 expression in the presence and absence of gene amplification. In vitro sensitivity of cell lines to OLX-209 is related to erbB-2 expression level. Normal bronchial epithelial cells were not sensitive. Effective treatment of lung cancer cell lines growing as xenografts in nude mice was shown with Calu-3 (a lung adenocarcinoma line with high levels of p185(erbB-2) caused by gene amplification) and three other lung adenocarcinomas (A549, NCI-H1466, and 201T) with lower levels of p185(erbB-2) and no gene amplification. The 201T cell line was isolated recently from a lung tumor with erbB-2 expression in the original tumor. The results of this study indicate that patients with erbB-2-positive, non-small cell lung cancer should be included in clinical trials of OLX-209.
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PMID:Activity of anti-erbB-2 recombinant toxin OLX-209 on lung cancer cell lines in the absence of erbB-2 gene amplification. 981 93


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