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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review considers the biology of the type 1 growth factor receptor family which is increasingly recognised as important in the control of normal cell proliferation and in the pathogenesis of human cancer. The family currently comprises three closely related members: the epidermal growth factor (EGF) receptor, c-erbB-2 and c-erbB-3, all of which show abnormalities of expression in various human tumours. The family of factors related to EGF has also expanded recently and now includes transforming growth factor alpha, heparin-binding EGF, amphiregulin, cripto and heregulin, as well as several other potential ligands for the c-erbB2-2 receptor. The involvement of these receptors and growth factors in human cancer has implications for the design of novel forms of therapy for cancer, and we review recent advances and future avenues for investigation.
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PMID:The type 1 (EGFR-related) family of growth factor receptors and their ligands. 135 72

c-erbB-3 is a member of the type I family of growth factor receptors which includes the epidermal growth factor (EGF) receptor and c-erbB-2. Whereas for EGF receptor and c-erbB-2 the expression patterns in normal tissues are well documented, there is currently little information available about the sites of c-erbB-3 expression. In order to examine the normal tissue distribution of c-erbB-3, polyclonal antibodies were raised against eight synthetic peptides corresponding to distinct sites on the intracellular domain of c-erbB-3. Of these, three produced antibodies which reacted with a 160-kDa protein on immunoblots of human embryonal cells (293 cells) transfected with the cDNA encoding c-erbB-3, and two of the three antibodies immunoprecipitated a protein of similar size from the same cells. These antibodies were used for immunochemical staining of a wide variety of normal human adult and fetal tissues employing formalin-fixed, paraffin-embedded material. The c-erbB-3 protein was identified in cells of the gastrointestinal, reproductive, respiratory and urinary tracts as well as the skin, endocrine and nervous system in a distribution distinctly different from that observed for EGF receptor and c-erbB-2. The level of expression of the mRNA for c-erbB-3 was also examined in extracts of a selection of fetal tissues. In general the sites of mRNA and protein expression were concordant.
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PMID:Expression of the c-erbB-3 protein in normal human adult and fetal tissues. 137 11

The responsiveness of estrogen receptor (ER)-positive breast cancer to endocrine therapy is frequently reduced in cells over-expressing c-erbB-2. Stimulation of ER suppresses c-erbB-2, indicating that estrogen controls the activity of c-erbB-2. Heregulin (HRG) has been described to bind to c-erbB-3/c-erbB-4 and to stimulate c-erbB-2. Here we describe the effects of HRG on cell growth and on ER and c-erbB-2 expression in breast cancer cell lines containing distinct levels of c-erbB-2 and ER (BT-474: c-erbB-2 , ER+; MDA-MB-361: c-erbB-2++, ER++; MCF-7: c-erbB-2+, ER ). Proliferation of estrogen-stimulated, c-erbB-2 and ER-positive cells is inhibited by HRG in a dose-dependent manner. In addition, HRG dose-dependently inhibits ER expression. Estrogen, however, inhibits c-erbB-2. Estrogen-mediated down-regulation of c-erbB-2 is most pronounced in MCF-7 but weaker in BT-474. In the latter cells HRG efficiently blocks the estrogenic effect on c-erbB-2. In MCF-7 cells, however, the inhibition of c-erbB-2 cannot be completely reverted by HRG. This modulation occurs in all 3 cell lines at protein, RNA and transcriptional levels, suggesting that the activity of the c-erbB-2 promoter, which contains an estrogen-responsive region, is affected by HRG. The intensity of the mutual inhibition between the HRG/c-erbB-2 and the estrogen/ER system depends on the relative levels of ER and c-erbB-2 expression in the respective cell lines.
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PMID:Bidirectional interactions between the estrogen receptor and the cerbB-2 signaling pathways: heregulin inhibits estrogenic effects in breast cancer cells. 759 Dec 67

Limited information is available concerning the involvement of growth factor receptors and their ligands in the pathogenesis of human pancreatic cancer. We analyzed 12 human pancreatic cancer cell lines by Northern blot analysis for the expression of 9 receptor tyrosine kinase (RTKs) and 6 growth factors. The effect of a monoclonal antibody (MAb) against transforming growth factor-alpha (TGF-alpha) on in vitro pancreatic cancer cell growth was also assessed, mRNA for EGF-R, c-erbB-2 and c-erbB-3 was expressed in 12 (100%), 12 (100%), and 7 (58%), respectively, of the cell lines examined. In addition, 8 (67%) cell lines expressed the c-met/receptor for hepatocyte growth factor. As for ligands, TGF-alpha mRNA was detected in 10 (83%) cell lines; MAb against TGF-alpha inhibited growth of the 2 cell lines examined. Furthermore, mRNA for amphiregulin (AR) was expressed in 10 (83%) cell lines. Coexpression of TGF-alpha, AR, and EGF-R was observed in 9 (75%) cell lines. These results support the concept that several specified types of RTKs and their ligands are closely involved in regulation of the growth of human pancreatic cancer cells.
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PMID:Frequent expression of genes for receptor tyrosine kinases and their ligands in human pancreatic cancer cells. 759 66

Immunohistochemical expression of EGF-R, c-erbB-2 and c-erbB-3, members of the type-1 family of receptor tyrosine kinases, were investigated in 67 primary ovarian-tumour samples (46 malignant, 8 borderline and 13 benign), and related to tumour clinicopathological features. The incidence of all 3 receptor proteins was highest in overtly malignant tumours. No significant correlations were observed between either EGF-R or c-erbB-3 and clinical parameters such as tumour stage, differentiation or extent of debulking surgery, but c-erbB-2 was significantly associated with several indicators of prognosis, including early stage and good/moderate differentiation in optimally debulked tumours. Multiple expression of c-erbB receptor proteins was also significantly higher in malignant tumours compared with borderline and benign tumours. Early-stage tumours were also more likely to express multiple c-erbB-receptor proteins than were late-stage tumours. Co-expression of EGF-R with c-erbB-2, and c-erbB-2 with c-erbB-3 was significantly greater in malignant tumours than in borderline or benign tumours, and within the malignant tumour group, positive associations were observed between EGF-R and c-erbB-3, also between c-erbB-2 and c-erbB-3. Because of the evidence of increased expression of individual c-erbB proteins as well as multiple expression of this family of growth-factor receptors in malignant ovarian tumours, we hypothesize that stimulation by the appropriate ligands may confer a selective advantage to cells expressing more than one receptor. Increased expression of c-erbB growth-factor receptors in malignancy may mediate increased propensity for tumour development.
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PMID:c-erbB growth-factor-receptor proteins in ovarian tumours. 762 9

To verity the role of metastasis-related nm23 genes in carcinogenesis and progression of ovarian carcinoma, we analyzed the mRNA levels of the nm23 genes of both isoforms, -H1 and -H2, together with those of the epidermal growth factor receptor, the c-erbB-2, and the c-erbB-3 genes in 45 ovarian carcinomas and 5 benign cystadenomas. Expressions of nm23 gene products/nucleoside diphosphate kinases, epidermal growth factor receptor, erbB-2 protein, and sex steroid receptor status in ovarian carcinomas were also examined by immunohistochemistry. The mRNA levels of nm23-H1 and nm23-H2 were higher in carcinoma tissues compared with benign tumors (H1, P < 0.01). The mRNA levels of c-erbB-2 and c-erbB-3 were also elevated in carcinoma tissues, and there was a positive correlation between mRNA levels of the nm23-H1 and the c-erbB-2 genes (r = 0.58; P < 0.05). Correlation of immunohistochemical staining between nucleoside diphosphate kinases and erbB-2 protein was also observed in ovarian carcinoma tissues. Sex steroid receptor positivity was related to a higher expression of nucleoside diphosphate kinases. Expression levels of the nm23 genes in ovarian carcinomas were not related to either histological subtype or local extension and peritoneal dissemination. Among stage III ovarian carcinomas, however, tumors possessing lymph node metastasis showed significantly lower nm23-H1 mRNA levels than those without nodal involvement (P < 0.05). Stage IV carcinomas also exhibited lower nm23-H1 and nm23-H2 expression levels compared with other stages (P < 0.05). These results suggest that expression of the nm23 genes, especially nm23-H1, is activated, accompanied by c-erbB-2 and c-erbB-3 overexpressions, in early stages of the carcinogenic process of ovarian carcinoma and reduction of nm23-H1 expression occurs in association with lymph nodal and/or distant metastasis.
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PMID:Expression of metastasis-related nm23-H1 and nm23-H2 genes in ovarian carcinomas: correlation with clinicopathology, EGFR, c-erbB-2, and c-erbB-3 genes, and sex steroid receptor expression. 790 45

The type I growth factor receptor family has been found to play an important role in the control of normal growth and differentiation. Moreover, the epidermal growth factor receptor and the c-erbB-2 oncogene seem to be implicated in the pathogenesis and behaviour of several cancers, including breast cancer. c-erbB-3 is a new member of the type I receptor family for which there is currently little information available on its expression in neoplastic tissues, and on its possible prognostic significance. This study was undertaken to define the prognostic value of c-erbB-3 expression in a series of node-negative breast cancer (NNBC) patients when compared, by multivariate analysis, with expression of the c-erbB-2 protein and conventional clinicopathological features. cerbB-3 was recognised by the novel monoclonal antibody RTJ1, whereas c-erbB-2 was detected by the polyclonal antibody 21N, using immunocytochemical methods. We found that overexpression of c-erbB-3 occurs frequently in NNBC. Overall, 138 of 212 carcinomas (65%) had some degree of membrane RTJ1 staining, and 28 (13%) showed strong and generalised positivity ( ). Twenty-four per cent of carcinomas had membrane 21N staining, and 12% presented strong and generalised positivity ( ). c-erbB-3 protein expression was significantly associated only with that of c-erbB-2 (P = 0.05), whereas 21N positivity was significantly associated with small tumour size (P = 0.02) and ductal histotype (P = 0.04). No significant correlation between expression of either receptor proteins or relapse-free survival was observed after a median follow-up of 63 months. Applying multivariate analysis, only tumour size approached significance. Our results indicate that analysis of expression of c-erbB-3 and c-erbB-2 alone do not seem to be useful in identifying patients with NNBC at different risk of relapse or death.
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PMID:c-erbB-3 and c-erbB-2 protein expression in node-negative breast carcinoma--an immunocytochemical study. 790 13

c-erbB-3 is a member of the type I (EGF receptor-related) family of growth factor receptors for which no ligand has been identified. To facilitate ligand stimulation we have constructed a chimeric receptor which possesses an activatable kinase and promotes the growth of NIH 3T3 fibroblasts. In this study we have shown that SHC and phosphatidylinositol 3'-kinase bind to the activated EGF receptor/c-erbB-3 chimera. Whereas p85 is not phosphorylated to a significant extent, SHC appears to be a major substrate for phosphorylation on tyrosine. In contrast to EGF receptor and c-erbB-2, we were unable to detect binding of activated c-erbB-3 to GRB2. Using synthetic peptides corresponding to each of 13 potential phosphorylation sites on c-erbB-3, we have shown that tyrosine 1309 is responsible for SHC binding. Peptides containing the motif YXXM inhibit p85 association. By comparison with recently reported SHC binding sites on Middle T antigen and Trk we have identified a SHC binding motif, NPXY.
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PMID:Identification of c-erbB-3 binding sites for phosphatidylinositol 3'-kinase and SHC using an EGF receptor/c-erbB-3 chimera. 802 68

The c-erbB-3 gene is a member of the EGF receptor family of membrane tyrosine kinases. Previous work has shown that the expression of this gene is frequently unregulated in human breast carcinoma-derived cell lines and in tumour biopsy material. As there is no evidence of gene amplification, we decided to examine the control of c-erbB-3 transcription in overexpressing cells. In this paper we describe the cloning of the c-erbB-3 promoter and its functional analysis within mammary-derived cell lines. We show that the promoter is more active in overexpressing cells and this is largely due to the action of the OB2-1 transcription factor which we have recently identified as mediating overexpression of the c-erbB-2 promoter in similar cell lines.
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PMID:Transcriptional regulation of the c-erbB-3 gene in human breast carcinoma cell lines. 824 42

In order to assess the specificity of biotinylated anti-c-erbB-3 antibody, screening was performed on a series of tumour cell lines and lymphocytes. Staining was found to be consistent, with good reproducibility. Twenty-nine consecutive breast cancer samples were obtained from women treated with tamoxifen and undergoing elective mastectomy. Twenty-eight invasive ductal carcinomas and 1 DCIS were stained for c-erbB-3 expression: 2 were grade I (Bloom and Richardson), 15 grade II, and 11 grade III tumours, 1 being unclassified; 16 were axillary node positive and 10 node negative; in 2 cases no nodes were sampled. Tumours examined by flow cytometry were stained with cytokeratin FITC antibody and the cytokeratin-positive population gated. Using Mann-Whitney analysis no association was seen between c-erbB-3 expression and Bloom and Richardson grade or axillary node status. In the tumour samples c-erbB-3 expression was found to show as association with EGF-R (P = 0.021 r2 = 0.16), PgR (P = 0.02, r2 = 0.16), c-myc (P < 0.0001, r2 = 0.5), c-jun (P = 0.001, r2 = 0.4) and c-fos (P = 0.001, r2 = 0.5) but not with c-erbB-2 (P = 0.2, r2 = 0.06), ER (P = 0.4, r2 = 0.02) or p53 1801 (P = 0.05, r2 = 0.2). Expression of c-erbB-3 may not be an independent marker of prognosis, but it is associated with other markers of poor prognosis and early cellular events linked with aberrant growth and differentiation.
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PMID:A flow cytometric study of c-erbB-3 expression in breast cancer. 853 73


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