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)

Promoter elements accounting for HER2 (c-erbB-2/neu) overexpression were searched for in several human breast cancer cell lines (MDA-453, BT-474, ZR-75-1, MCF-7) known to express constitutively a 30-fold range in HER2 transcripts per gene copy. HER2 overexpressing cells showed a single prominent DNase I hypersensitive site near a conserved and hitherto unrecognized ets response element (GAGGAA), located 38 bases down-stream from the CAAT box and directly 5' of the TATA box in the human HER2 promoter. Transient transfection of HER2 promoter constructs (0.125, 0.5, and 2.0 kilobase pairs (kb)) demonstrated that the most proximal promoter region (0.125 kb) was capable of conferring up to 30-fold enhanced activity in HER2-overexpressing cell lines relative to low HER2-expressing control lines. Site-directed mutagenesis of the ets response element (GAGGAA-->GAGAGA) caused a > or = 60% reduction in promoter activity affecting at least 0.5 kb of upstream HER2 regulatory sequence. Gel-shift assays with nuclear extracts and oligonucleotide sequences spanning the 0.125-kb promoter region detected an ETS-immunoreactive complex, present most abundantly in cells overexpressing HER2, whose high-affinity binding depended on the GAGGAA response element. Methylation interference confirmed the ETS-specific pattern of protein binding by this complex to guanine bases in the ets response element. UV cross-linking and immunoprecipitation implicate a approximately 60-kDa ETS protein, and candidate ETS genes expressed in these breast cancer cells include GABP alpha, elk-1, elf-1, and PEA3.
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PMID:Binding of an ETS-related protein within the DNase I hypersensitive site of the HER2/neu promoter in human breast cancer cells. 791 92

Prompted by recent findings on the amplification of c-erbB-2 (HER-2, neu) oncogene in salivary gland tumours, the present study was conducted to analyse the expression of c-erbB-2 in both benign and malignant salivary gland tumours, with special emphasis on its prognostic significance and relevance to clinical data. A series of 219 salivary gland tumours (with pertinent clinical data), including 103 malignant and 116 benign tumours, were analysed immunohistochemically using a monoclonal antibody to c-erbB-2 protein. Smoking was not a risk factor for malignant tumours, smokers being equally represented in both groups: 18.4 and 21.6% in malignant and benign series, respectively. Multi-variate analysis of the extensive clinical data did not disclose any other risk factors either. Cellular membrane staining for c-erbB-2 was present in 36 (35.0%) carcinomas and 41 (35.3%) benign tumours. Among the malignant tumours, c-erbB-2 expression was most frequent in adenoid cystic carcinomas (57.7%) followed by adenocarcinomas (39.3%). Among the benign tumours, 47% of Warthin's tumours and 33.3% of the pleomorphic adenomas showed staining for c-erbB-2. The highest prevalence of c-erbB-2 immunoreactivity was seen in adenocarcinomas of the parotid gland (81.8%), followed by undifferentiated carcinomas (75%) and adenoid cystic carcinomas (73.3%) in that location. Age at diagnosis, number of recurrences, analysis as well as time to relapse or metastases were similar in c-erbB-2-positive and -negative malignant tumours. Also mortality in c-erbB-2-positive and -negative salivary gland cancers was similar.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:c-erbB-2 oncogene expression in salivary gland tumours. 791 30

The erbB-2 (or HER-2 or neu) gene is amplified and overexpressed in approximately one-third of cancers of the breast, stomach, and ovary. Evidence is accumulating that erbB-2 overexpression is associated with decreased survival of breast cancer patients. In an effort to understand how erbB-2 overexpression might impart a more malignant potential to breast cancer cells, we have searched for evidence of changes in gene expression associated with erbB-2 overexpression. Using differential screening of a complementary DNA library we identified several complementary DNAs that represent mRNAs the expression of which may vary according to erbB-2 level. One complementary DNA was studied in detail. The mRNA encoding the ribosomal protein L19 (1.9 kilobases) was more abundant in breast cancer samples that express high levels of erbB-2 (P < 6 x 10(-7)). The level of L19 mRNA expression varied over a 1- to 64-fold range among the tumor samples. No evidence of gene amplification for L19 was identified. The L19 overexpression in these breast tumor samples was not associated with the increased expression of the mRNAs for other ribosomal proteins (S16 and L26).
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PMID:High-level expression of the ribosomal protein L19 in human breast tumors that overexpress erbB-2. 809 82

Bispecific monoclonal antibodies (BsmAb) with specificity for tumor Ag and effector cell trigger molecules have been shown to redirect the cytotoxicity of several peripheral blood mononuclear cell populations against relevant tumor. The BsmAb, 2B1, binds to the extracellular domain of the c-erbB-2 gene product of the HER2/neu proto-oncogene and to CD16. In this report, the binding and cytotoxic characteristics of 2B1 are presented. Maximal saturation binding of 2B1 to PBL and c-erbB-2 expressing SK-OV-3 cells occurred in the 1 microgram/ml concentration range. However, substantial lysis potentiation was observed at 1000-fold lower BsmAb concentrations. Optimal tumor lysis was obtained when the BsmAb, PBL, and target cells were continuously coincubated. When PBL were franked with 2B1, washed, and added to labeled targets, substantially less lysis was observed. These results suggest that the best way to therapeutically exploit the cytotoxic attributes of 2B1 may be to obtain continuous BsmAb exposure to tumor. Approaches based on franking of this BsmAb to PBL may not be warranted.
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PMID:Binding and cytotoxicity characteristics of the bispecific murine monoclonal antibody 2B1. 810 70

p185HER2, the product of the c-erbB-2 or HER2 gene, is a membrane-bound tyrosine kinase that has structural similarity to the epidermal growth factor receptor. Functionally, interaction of HER2 with its ligand or p185HER2 antibodies affects the growth and differentiation of HER2-expressing breast cancer cell lines. As p185HER2 is also expressed in human lung cancers and human lung cancer cell lines, we hypothesized that these cell lines would also respond to p185HER2 antibodies. To test this hypothesis, we cultured human non-small cell lung cancer cell lines in the presence of a p185HER2 monoclonal antibody called 4D5. 4D5 inhibited the growth of p185HER2-expressing cell lines in a dose-dependent fashion. In addition, BEAS.2B, a p185HER2-nonexpressing bronchial epithelial cell line, was transfected with the HER2 cDNA, resulting in high-level p185HER2 expression, and growth of BEAS.HER2 was now inhibited by 4D5 exposure. Mechanistically, 4D5 appeared to have a weak agonist effect on the tyrosine kinase function of p185HER2, as exposure of p185HER2-expressing cell lines to 4D5 resulted in increased p185HER2 phosphorylation. Furthermore, inhibition of tyrosine kinase function with Genistein reversed the 4D5-induced growth inhibition. Therefore, 4D5 can regulate the growth of p185HER2-expressing lung cancer cell lines through agonist effects on p185HER2.
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PMID:Inhibition of human lung cancer cell line growth by an anti-p185HER2 antibody. 810 37

Competitive polymerase chain reaction (PCR) systems were developed for rapid and quantitative estimation of HER-2 (c-erbB-2) and INT-2 oncogene amplification in paraffin-embedded ovarian cancer tissue samples. The beta-globin gene was used as reference and DNA from paraffin-embedded placenta tissue as single copy control. Reliability of the PCR method could be demonstrated by comparing dot blot data with PCR data of identical tumour samples. The PCR method was used to determine HER-2 and INT-2 copy numbers in 196 ovarian cancer samples. HER-2 and INT-2 were found to be amplified in 40 and 19%, respectively. In 8% HER-2 copy numbers were greater than five, but no high INT-2 copies were noted. Kaplan-Meier estimates did not reveal significant association with overall survival. Indirect correlation between HER-2 and INT-2 amplification was observed. The present PCR system is a valuable method for prospective and retrospective studies.
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PMID:HER-2 and INT-2 amplification estimated by quantitative PCR in paraffin-embedded ovarian cancer tissue samples. 810 39

Normal and neoplastic human intracranial tissues were examined by immunohistochemistry for c-erbB-2/HER-2 protein expression. Positive staining was observed in 1/41 gliomas, 1/2 medulloblastomas, 1/1 germinoma, 11/16 meningiomas, 1/3 anaplastic meningiomas and 11/19 metastatic brain carcinomas. No positive staining was observed in normal intracranial tissues. Thus, the expression of the c-erbB-2/HER-2 protein is limited to intracranial tumour tissues, principally meningiomas and metastatic carcinomas to the brain.
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PMID:C-erbB-2/HER-2 protein in human intracranial tumours. 810 41

This report describes the isolation and recombinant expression of a cDNA clone encoding HER4, the fourth member of the human epidermal growth factor receptor (EGFR) family. The HER4/erbB4 gene encodes a 180-kDa transmembrane tyrosine kinase (HER4/p180erbB4) whose extracellular domain is most similar to the orphan receptor HER3/p160erbB3, whereas its cytoplasmic kinase domain exhibits 79% and 77% identity with EGFR and HER2/p185erbB2, respectively. HER4 is most predominantly expressed in several breast carcinoma cell lines, and in normal skeletal muscle, heart, pituitary, brain, and cerebellum. In addition, we describe the partial purification of a heparin-binding HER4-stimulatory factor from HepG2 cells. This protein was found to specifically stimulate the intrinsic tyrosine kinase activity of HER4/p180erbB4 while having no direct effect on the phosphorylation of EGFR, HER2, or HER3. Furthermore, this heparin-binding protein induces phenotypic differentiation, and tyrosine phosphorylation, of a human mammary tumor cell line that overexpresses both HER4 and HER2. These findings suggest that this ligand-receptor interaction may play a role in the growth and differentiation of some normal and transformed cells.
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PMID:Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. 838 26

A 28-base phosphodiester triple helix-forming oligonucleotide, mostly G and A containing, targeted to a polypurine tract interrupted by a purine-pyrimidine inversion, situated upstream from the TATA box of the promoter of the human HER2 gene, was conceived by computer modeling. The "energetically best choice" was oligo 28(C), which formed the triple helix in vitro, as proved by gel retardation and Fourier transform infrared spectroscopy. When administered as a complex with lipofectin, fluorescence confocal microscopy and electrophoresis confirmed the delivery and persistence of this unprotected oligonucleotide inside MCF7 (breast cancer) cells. At a concentration of 2 microM, the oligonucleotide reduced within 6 h the HER2 mRNA level to 42% (Northern blot) but did not interfere with the transcription of a housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase. During the first day of administration at 0.22 microM, it lowered to 59% the HER2 protein in treated, as compared to nontreated, cells (ELISA). The effect was sequence specific when compared to that of five different negative controls, and it was target selective when compared to the expression of a related, nontargeted protein, the epidermal growth factor receptor. By day 2, the inhibitory effect was overcome by replenishment reactions.
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PMID:Temporary ex vivo inhibition of the expression of the human oncogene HER2 (NEU) by a triple helix-forming oligonucleotide. 856 64

The activated neu (HER2/c-erbB-2) oncogene is extremely potent in inducing mammary cancer. For example, neu induces greater than 200 times as many tumors as the activated ras oncogene when directly introduced into in situ rat mammary epithelial cells using replication-defective retroviral vectors. In order to characterize mechanisms underlying this potency, we sought to identify uniquely overexpressed genes in neu-initiated tumors that were not overexpressed in tumors induced by weaker initiating agents, including activated ras and the chemical carcinogens dimethylbenz[a]anthracene and N-nitroso-N-methylurea. Several genes, including those encoding keratin K7 and the u haplotype of MHC class I RT1-A, were found to be overexpressed in neu-initiated carcinomas as well as in mammary carcinomas induced by other agents, when compared to their expression in normal mammary tissue. One gene, however, encoding a member of the lipocalin and calycin protein families, was 12-fold overexpressed in neu mammary tumors and was not overexpressed in ras or chemically induced carcinomas. This uniquely overexpressed gene was termed neu-related lipocalin (NRL). NRL protein was produced in a baculovirus system, purified and used to generate polyclonal antibodies. Western blot analysis indicate that neu-initiated mammary carcinomas express abundant NRL protein when compared to other mammary tumors.
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PMID:Overexpression of neu-related lipocalin (NRL) in neu-initiated but not ras or chemically initiated rat mammary carcinomas. 857 Jan 73


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