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)

Oral mucosal lichen planus (OMLP) is a well recognized mucosal disease with unknown etiology. Considerable controversy exists as to whether OMLP is intrinsically premalignant, or if the disorder facilitates the development of oral mucosal squamous cell carcinoma (OMSCC) by external factors. The aim of the present study was to investigate the expression of c-erbB-2 protein in the keratinocytes of initial biopsies or oral mucosal disorders diagnosed as OMLP with no evidence of epithelial dysplasia, and to compare the results with the expression of c-erbB-2 protein in subsequent biopsies obtained from the same patients. These results were compared with the findings from control groups (patients with dysplasia with no evidence of OMLP, patients with OMSCC with no evidence of OMLP and normal oral mucosa). The expression of the c-erbB-2 protein was evaluated by immunohistochemical staining of the gene product with the avidin-biotin-complex method using paraffin-embedded tissues sections. Five of the initial biopsies from patients with OMLP expressed the c-erbB-2 protein and one did not. None of the OMLP cases that subsequently showed evidence of dysplasia expressed the c-erbB-2 protein, and of the three OMSCC specimens from the patients with OMLP, two were negative and one expressed c-erbB-2 protein. The specimens from the control groups all expressed the c-erbB-2 protein. The results indicated the probability of the absence of c-erbB-2 staining being an indication of a potential for neoplastic transformation in OMLP with dysplastic changes.
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PMID:Expression of c-erbB-2 protein in keratinocytes of oral mucosal lichen planus and subsequent squamous cell carcinoma. 883 Oct 62

c-erbB-3 is a new member of the Type I growth factor receptor family that includes epidermal growth-factor receptor (also called c-erbB-1) and HER-2/neu (also called c-erbB-2). Frequency and significance of c-erbB-3 overexpression in lung cancers have not been reported previously. A series of 549 cases of primary lung carcinomas were immunostained with a monoclonal anti-human c-erbB-3 antibody (Clone RTJ.1) using formalin-fixed, paraffin-embedded archival tissue. Sharp membranous staining or punctate cytoplasmic staining was interpreted as positive and scored 0 (< 5% of tumor cells), 1 (5-9%), 2 (10-49%), or 3 (> or = 50%). Medical records were reviewed for clinical data, including stage and survival. Actuarial cumulative survival analysis with the Mantel-Cox test was performed on 443 cases that had a single primary site in the lung of pure non-small cell carcinoma (adenocarcinoma, squamous cell carcinoma, large cell carcinoma) and that also had follow-up data for more than 3 months. In all stages, squamous cell carcinoma showed the greatest rate of high c-erbB-3 positivity (score, 3) (34/119; 28.6%), followed by adenocarcinoma (41/256; 15.9%) and large cell carcinoma (7/66; 10.6%). Patients with high c-erbB-3 expression (score, 3) survived for significantly shorter times than did patients with low c-erbB-3-expression (score, 0-2) in Stages III and IV (P = 0.002), but not in Stage I or II non-small cell lung carcinomas. In conclusion, high c-erbB-3 expression in advanced non-small cell lung carcinomas might be an adverse prognostic factor. This finding suggests that c-erbB-3 might be a potential target for molecular therapy in advanced non-small cell lung carcinomas.
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PMID:High c-erbB-3 protein expression is associated with shorter survival in advanced non-small cell lung carcinomas. 912 20

The epidermal growth factor (EGF) receptor is well known as a mediator of mitogenic signaling and its tyrosine kinase activity has been suggested as a viable target in cancer chemotherapy. To explore the consequences of abolishing the kinase activity of this receptor, we have utilized a potent and specific inhibitor of the enzyme, PD 153035, to sustain a long-term suppression of its activity. This compound inhibits EGF receptor autophosphorylation in cells with an IC50 in the low nanomolar range and does not block PDGF or FGF receptor kinase until concentrations are greater than 10 microM. [1] Human epidermoid carcinoma A431 cells were grown in the presence of PD 153035 and were passed weekly until cells grew in the presence of 1 microM inhibitor. These cells, referred to as A431R, showed a remarkable change in morphology, becoming flattened and spread out. A comparison of the sensitivity of EGF receptor autophosphorylation to PD 153035 between A431 and A431R showed a similar dose response, indicating that the cells had not developed any defect in the kinase which might make it resistant to the inhibitor. Likewise, EGF receptor autophosphorylation in response to exogenously added EGF, as well as receptor internalization, was similar between the two cell lines. Furthermore, analysis of A431R cells by flow cytometry showed no significant change in DNA content or percentage of cells in any one phase of the cell cycle compared to the parent line. 125I-labeled EGF/receptor binding studies showed that receptor number in the A431R cells was equivalent to that of the parent line; however, the Scatchard plot was linear, in contrast to the typical biphasic plot obtained with the parent cells, implying a loss of high-affinity receptors. Cytoskeletal preparations from both cell lines indicated that the A431R had fourfold less EGF receptor associated with the cytoskeleton than A431. This was accompanied by a remarkable increase in polymerized actin stress fibers throughout the A431R cells, which most likely accounts for their flattened morphology. The A431R cells also exhibited a twofold increase in the expression of focal adhesion kinase, which is consistent with a greater contact area for their cell surface and increase in focal adhesions. Finally, although the A431R cells have a doubling time of 24 h, similar to that of the parent line, these cells stop growing as the monolayer approaches confluence, reminiscent of the contact inhibition seen in nontransformed cells. These data indicate that long-term suppression of the EGF receptor tyrosine kinase activity in A431 human epidermoid carcinoma results in certain cellular properties which are more consistent with a differentiated and nontransformed phenotype.
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PMID:Cytoskeletal and morphological changes associated with the specific suppression of the epidermal growth factor receptor tyrosine kinase activity in A431 human epidermoid carcinoma. 919

Overexpression of c-erbB-2/neu/HER-2 oncoprotein, a receptor tyrosine kinase, has been demonstrated in a variety of human cancers. To elucidate the involvement of c-erbB-2 in human skin carcinogenesis, we examined expression of the protein in skin samples from five cases of keratoacanthoma (KA), 10 of actinic keratosis (AK), 24 of squamous cell carcinoma (SCC) and 10 of basal cell carcinoma (BCC) and five samples of normal epidermis, using an immunohistochemical method on formalin-fixed, paraffin-embedded sections. Expression of c-erbB-2 was also examined in cultured SCC cell lines, a premalignant cell line and in cultured normal keratinocytes. Normal epidermal cells showed no or very little c-erbB-2 protein, but the covering epidermal layer of some tumours showed a few strongly positive cells. Samples of KA and AK showed barely detectable c-erbB-2 protein in only a few cases. Twenty of the 24 cases of SCC had elevated expression of c-erbB-2 protein, with a tendency to more positive cells in metastatic lesions. Five of the 10 cases of BCC stained for c-erbB-2 but more weakly than those of SCC. Reaction products of the positive cells were seen in the cytoplasm. All three cultured SCC cell lines stained for c-erbB-2 protein more strongly than the premalignant HaCaT or normal keratinocytes. Our results indicate the possible involvement of c-erbB-2 overexpression in the malignant conversion of keratinocytes.
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PMID:Increased level of c-erbB-2/neu/HER-2 protein in cutaneous squamous cell carcinoma. 921 24

The study reports the first case of basaloid squamous cell carcinoma (BSCC) involving both the oral mucosa and the tuberosity area of the maxilla. The tumour showed many histological similarities to cases previously reported, though mitoses were not frequent. The immunoreactivity for cytokeratin, S-100, vimentin, Ki-67, p53, c-erbB-2 and bcl-2 was also investigated. Immunostaining for the bcl-2 protein showed a high extent of positive cells, although only a moderate staining intensity. Staining for c-erbB-2 was negative. The pathological findings and the immunoreactivity may indicate that BSCC is not as high a grade carcinoma as previously suggested. Additional studies are thus clearly needed to confirm or reject this impression.
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PMID:Basaloid squamous cell carcinoma of the maxilla. 968 80

The tyrosine kinase inhibitors PD 69896, 153717, and 158780, which belong to the chemical class 4-[ar(alk)ylamino]pyridopyrimidines, have been characterized with respect to enzymology, target specificity, and antiproliferative effects in tumor cells. These compounds were competitive inhibitors with respect to ATP against purified epidermal growth factor (EGF) receptor tyrosine kinase and inhibited EGF receptor autophosphorylation in A431 human epidermoid carcinoma with IC50 values of 2085, 110, and 13 nM, respectively. Onset of inhibition was immediate once cells were exposed to these compounds, whereas recovery of receptor autophosphorylation activity after the cells were washed free of the compound was dependent on inhibitory potency. Thus, full activity returned immediately after removal of PD 69896 but required 8 hr after exposure to PD 158780. PD 158780 was highly specific for the EGF receptor in Swiss 3T3 fibroblasts, inhibiting EGF-dependent receptor autophosphorylation and thymidine incorporation at low nanomolar concentrations while requiring micromolar levels for platelet-derived growth factor- and basic fibroblast growth factor-dependent processes. PD 158780 inhibited heregulin-stimulated phosphorylation in the SK-BR-3 and MDA-MB-453 breast carcinomas with IC50 values of 49 and 52 nM, respectively, suggesting that the compound was active against other members of the EGF receptor family. The antiproliferative effects of this series of compounds against A431 cells correlated precisely with the inhibitory potency against EGF receptor autophosphorylation. PD 158780 reduced clone formation in soft agar of fibroblasts transformed by EGF, EGF receptor, or the neu oncogene but not ras or raf, further demonstrating its high degree of specificity. Finally, this compound was active against clone formation in several breast tumors having different expression patterns of the erbB family, indicating an anticancer utility in tumors expressing these receptors.
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PMID:Biochemical and antiproliferative properties of 4-[ar(alk)ylamino]pyridopyrimidines, a new chemical class of potent and specific epidermal growth factor receptor tyrosine kinase inhibitor. 935 88

The expression of c-erbB-1 and c-erbB-2 oncogenes were investigated by immunohistochemistry using monoclonal antibodies to c-erbB-1 and c-erbB-2 protein in 43 cases of basal cell carcinoma (BCC) and 26 cases of squamous cell carcinoma (SCC). We found that the expression of c-erbB-1 oncogene in all BCC increased by different degrees and the expression of c-erbB-2 oncogene in BCC was significantly reduced or lost when compared to that in normal epidermal cells. Furthermore, apparent negative and positive relationships were observed respectively between the tumor differentiation and the expression of c-erbB-1 and c-erbB-2 oncogenes in SCC. It is suggested that the abnormal expression of c-erbB-1 and c-erbB-2 oncogenes in BCC and SCC may play a role in the development of skin tumors. The pattern of the c-erbB-1 and c-erbB-2 oncogenes expression in SCC may assist in distinguishing the biological behavior and prognosis of SCC.
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PMID:The expression of c-erbB-1 and c-erbB-2 oncogenes in basal cell carcinoma and squamous cell carcinoma of skin. 938 20

The exact role of oncogenes and proto-oncogenes in the development of squamous cell carcinoma of the head and neck (SCCHN) is still debatable. The expression of the c-erbB-2, c-erbB-3 and c-erbB-4 members of the epidermal growth factor receptor family was examined in 16 fresh frozen tissue specimens of SCCHN using avidin-biotin complex immunohistochemistry, with monoclonal and/or polyclonal antibodies directed against each. Eight fresh frozen tissue specimens of normal oral mucosa were included as controls. Of the SCCHN examined, mixed membrane/cytoplasmic staining (moderate to intense) of c-erbB-2 was found in 14/16 cases (88%). When present in the specimen, immunopositive staining of c-erbB-2 was seen in some of the oral surface epithelial cell layers (basal, intermediate and/or superficial) as well as the tumour islands. Weak cytoplasmic staining of c-erbB-3 and c-erbB-4 was found in 13/16 (81%) and 11/16 (69%) cases respectively. When present in the specimen, c-erbB-3 and cerbB-4 immunopositive staining was seen in some of the oral surface epithelial cell layers (basal, intermediate and/or superficial) as well as the tumour islands. For the positive carcinomas for c-erbB-2, c-erbB-3 and c-erbB-4, the epithelium located near the carcinomas showed weak mixed membrane/cytoplasmic staining of c-erbB-2 in 5/14 cases (36%), weak cytoplasmic staining of c-erbB-3 in 7/13 cases (54%) and of c-erbB-4 in 3/11 cases (27%). All the normal control oral mucosa showed the same pattern of staining for c-erbB-2, c-erbB-3 and c-erbB-4 found in the epithelium located near the carcinomas. Only expression of c-erbB-2 was found to correlate with the increase in the tumour stage, while co-expression of c-erbB-2, c-erbB-3 and c-erbB-4 was found to correlate with the patient survival time in 25% of the carcinomas examined. The present study shows that a) expression of c-erbB-2, but not c-erbB-3 and c-erbB-4 correlates with the increase of the tumour stage b) co-expression of c-erbB-2, c-erbB-3 and c-erbB4 correlates with decreased survival time in some of the cases of SCCHN, but not the majority c) co-expression of the c-erbB family in normal oral mucosa as well as in the carcinoma may question whether the increased tendency for development of the disease is due to co-expression of c-erbB proto-oncogenes in head and neck lesions.
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PMID:Expression of c-erbB proto-oncogene family members in squamous cell carcinoma of the head and neck. 949 65

Transforming growth factor beta 1 (TGF beta 1) increases the phosphorylation of the epidermal growth factor (EGF) receptor and inhibits the growth of A431 cells, but the mechanism of TGF beta 1 signaling is unknown. Recent studies from this and other laboratories suggest a novel sphingomyelin signal transduction pathway (1-4). Ceramide, which is generated by sphingomyelinase action, can be deacylated to sphingoid bases, which are potential inhibitors of protein kinase C (PKC). Ceramide appears to have bioeffector properties. Cell-permeable ceramide analogs stimulate monocytic differentiation of human leukemia (HL60) cells (1), as well as the phosphorylation of the EGF receptor at Thr669 in A431 human epidermoid carcinoma cells (2). Further studies (3,4) demonstrate the existence of a ceramide-activated protein kinase (CAPK) that may mediate some of these aspects. The present studies aim to investigate the mechanism of TGF beta 1 signaling and to explore whether TGF beta 1's pathway involves activation of PKC by 1,2-Diacylglycerol (DAG) and/or stimulation of a CAPK by ceramide. Ceramide and DAG levels of A431 cells are determined by thin layer chromatography (TLC) after treatment with either TGF beta 1 or with EGF. 100 pM TGF beta 1 treatment for 1 hr increases the cellular contents of DAG 2-fold. 20 nM EGF treatment for 15 min decreases it 0.5-fold. Ceramide levels are reduced 2-fold by TGF beta 1 and almost unaffected by EGF. To evaluate the involvement of other components of signal transduction, the effects of TGF beta 1 and EGF on PKC activity are studied. 20 nM EGF decreases membrane PKC activity to 0.5-fold of controls, whereas 100 pM TGF beta 1 treatment of A431 cells increases this activity 4-fold. Modulation of PKC activity is paralled by translocation of the enzyme between the cytosol and the membrane as determined by Western immunoblot analysis. These studies suggest that TGF beta 1 and EGF may have regulatory effects on both sphingolipid and phospholipid metabolisms which could transmodulate both the CAPK and the PKC mediated signal tranduction pathways.
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PMID:The rise and fall of ceramide and 1,2-diacylglycerol (DAG): modulation by transforming growth factor-beta 1 (TGF beta 1) and by epidermal growth factor (EGF). 954 91

Thirty-seven samples of oral mucosa were analysed and divided histologically into groups of normal mucosa (6), hyperplastic lesions (6), dysplastic lesions (14), and squamous cell carcinoma (11). All lesions displayed some expression of c-erbB-2 but the distribution and intensity of expression varied strongly according to the differentiation. The lower the epithelial differentiation of the sample, the higher the expression of c-erbB-2 oncoprotein showing very strong staining in carcinoma samples. This suggests that in oral carcinoma, transformation might be related to c-erbB-2 interaction.
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PMID:Immunohistochemical analysis of the oncoprotein c-erbB-2 expression in oral benign and malignant lesions. 966 15


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