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

Amplification of the HER-2 (c-erbB-2) gene and overexpression of the p185HER-2 gene product is found in approximately one-third of primary human breast and ovarian cancers and is associated with a poor clinical outcome of early relapse and death. The HER-2 gene encodes a cell-surface growth factor receptor with intrinsic tyrosine kinase activity. Wild-type human HER-2 has been shown to act as a potent oncogene when over-expressed in mouse fibroblasts. Recent data suggest that the mechanism by which HER-2 mediates transformation requires the interaction of the epidermal growth factor (EGF) receptor. To test whether overexpression of normal human HER-2 can transform cells independently of the EGF receptor, we have introduced multiple copies of HER-2 into the EGF receptor-negative cell line, NR6, and have performed assays for both transformation and tumorigenicity. Engineered NR6 cells that overexpress the HER-2 gene product display a highly transformed and tumorigenic phenotype as compared with control cells. Additionally, a monoclonal antibody to the extracellular domain of the HER-2 receptor is able to inhibit the proliferation of the overexpressing cells in vitro as well as tumor growth in vivo. This study provides clear evidence that HER-2-mediated transformation can be achieved independently of the EGF receptor.
Oncogene 1992 Sep
PMID:Transformation mediated by the human HER-2 gene independent of the epidermal growth factor receptor. 135 48

Using permanent-section immunohistochemistry, we investigated the role of HER-2/neu in the development and progression of human breast cancer by measuring its overexpression in a series of hyperplastic (n = 30), dysplastic (n = 15), and malignant neoplastic (n = 708) lesions of ductal epithelium and by evaluating the relationships between overexpression and clinicopathologic features known to have prognostic significance in these lesions. The neoplasms included pure ductal carcinoma in situ (DCIS; n = 59) and infiltrating ductal carcinoma (IDC; n = 649). The latter were all node negative and stratified into IDC combined (n = 237) or not combined (n = 412) with a "significant amount" of DCIS (defined as DCIS greater than or equal to 10% of total tumor cellularity). Overexpression of HER-2/neu was not observed in any of the hyperplastic or dysplastic lesions. In contrast, it was present in 56% of pure DCIS and in 77% of the comedo subtype of this group. Only 15% of IDC overexpressed HER-2/neu. However, the rate of overexpression was significantly higher in the subset of IDC combined with DCIS compared with the subset of IDC not combined with DCIS (22% v 11%, respectively; P less than .0001). These results are consistent with the hypothesis that HER-2/neu plays a more important role in initiation than in progression of ductal carcinomas. They also suggest that overexpression decreases within individual tumors as they evolve from in situ to increasingly invasive lesions or, alternatively, that many invasive carcinomas arise de novo (ie, without progressing through a significant in situ stage) by mechanisms not involving HER-2/neu. In addition, overexpression of HER-2/neu was associated with several poor prognostic features (younger patient age, premenopause, negative estrogen receptor status, negative progesterone receptor status, and high nuclear grade) in the subset of IDC combined with DCIS. With one exception (negative estrogen receptor status) these associations were lost in IDC not combined with DCIS, also suggesting that the role of HER-2/neu changes during the progression of human breast cancer.
Hum Pathol 1992 Sep
PMID:Overexpression of HER-2/neu and its relationship with other prognostic factors change during the progression of in situ to invasive breast cancer. 135 64

In order to identify potential markers of malignancy in diagnostic respiratory cytopathology, c-myc and c-erbB-2 proto-oncogene expression was studied in fine needle aspirates from 14 consecutive fresh operation tissue samples (after surgical removal) representing lung tumors and a variety of other cell samples by in situ hybridization of 35S-labeled antisense and sense RNA c-myc and c-erbB-2 specific proto-oncogene probes. All 14 lung tumors showed c-myc expression and eight also showed c-erbB-2 expression. On average, the c-myc expression was about 4 times higher than that of c-erbB-2 (P less than 0.001). c-erbB-2 expression, confirmed also as a cytoplasmic membrane-bound reactivity by immunohistochemical stainings for c-erbB-2 oncoprotein, was significantly related to adenocarcinoma (P less than 0.025), whereas increasing tumor size correlated significantly with increasing c-myc expression (P less than 0.05). On average, all the tumor cell lines showed 2-fold expression of c-myc compared with the lung tumors (P less than 0.025). c-erbB-2 expression was found in six of 11 cell lines. High c-myc proto-oncogene expression was also found in broncho-epithelial cells and alveolar macrophages, and a low expression was found in lymphocytes but not in neutrophils, while none of these cells showed c-erbB-2 proto-oncogene expression. Our results demonstrate extensive c-myc proto-oncogene expression in both malignant and non-neoplastic proliferating cells, but not in terminally differentiated cells such as neutrophils. Therefore c-myc expression must also be related to general cell proliferation and not only malignancy per se. In marked contrast, c-erbB-2 proto-oncogene expression was found only in adenocarcinoma cells, and thus can be used as a marker for malignancy in diagnostic respiratory cytopathology.
Am J Respir Cell Mol Biol 1992 Sep
PMID:Evidence by in situ hybridization that c-erbB-2 proto-oncogene expression is a marker of malignancy and is expressed in lung adenocarcinomas. 135 55

The expression of p53 protein, oestrogen receptor protein, epidermal growth factor receptor (EGFR) and overexpression of the c-erbB-2 oncoprotein was examined in a series of 149 primary symptomatic breast carcinomas. Expression of p53 was present in 62 of 146 cases (42.5%) of the invasive carcinoma and one of three cases (33.3%) of ductal carcinoma in situ (DCIS) examined. Statistical associations of tumour oestrogen receptor positivity and lack of p53 protein expression, chi 2 = 19.78 (d.f. = 1), P less than 0.001, positive tumour p53 status and poor tumour grade; chi 2 = 14.1 (d.f. = 2), P less than 0.001, EGFR expression chi 2 = 7.07, (d.f. = 1), P less than 0.01 and tumour c-erbB-2 protein overexpression; chi 2 = 4.61 (d.f. = 1), P = 0.032 were identified. Expression of p53 is rare in invasive lobular carcinoma of classical type (8.3% of cases examined) in contrast to other common types of mammary carcinoma. Non-significant trends of p53 protein expression and increased regional tumour recurrence; chi 2 = 3.20 (d.f. = 1), P = 0.074 and also poorer patient survival; chi 2 = 3.76 (d.f. = 1), P = 0.053 were identified. p53 protein expression is a common event in human breast cancer and is present in both DCIS and invasive mammary carcinoma. Abnormal expression of p53 protein is a feature of both in situ and invasive breast carcinoma, implying that the abnormal p53 protein expression may be implicated in the early stages of mammary carcinoma progression.
Br J Cancer 1992 Sep
PMID:p53 protein expression in human breast carcinoma: relationship to expression of epidermal growth factor receptor, c-erbB-2 protein overexpression, and oestrogen receptor. 135 62

Twenty-four renal-cell carcinomas (RCC) and corresponding non-neoplastic kidney tissue were examined for amplification and expression of the HER-2/neu gene. Gene amplification was examined by slot-blot analysis, mRNA expression by in situ hybridization and Northern blot analysis, and protein expression by immunohistochemistry. Northern-blot analysis revealed lower expression of HER-2/neu mRNA in clear-cell (p less than 0.001) and compact (p less than 0.001) tumor subtypes, while chromophilic, chromophobic and tubulo-papillary subtypes did not show significant differences in HER-2/neu gene expression, as compared with non-neoplastic kidney tissues. HER-2/neu gene expression was not significantly associated with tumor stage. Low differentiation (G3) was associated with lower HER-2/neu gene expression, but the number of G3 cases was too small for statistical analysis. HER-2/neu gene amplification was not found in any of the tumors. The results of in situ hybridization and immunohistochemistry generally agreed with those of Northern-blot analysis. We conclude that HER-2/neu gene expression correlates with Thoenes' classification of RCC and may be inversely related to tumor differentiation; it is probably not involved in progression of RCC, in contrast to carcinomas of other locations (e.g. breast, ovary).
Int J Cancer 1992 Sep 09
PMID:Expression of HER-2/neu in renal-cell carcinoma. Correlation with histologic subtypes and differentiation. 135 55

Over-expression of the proto-oncogene HER-2 (c-erbB-2/neu) in ovarian, endometrial, and mammary carcinoma is an indicator of poor prognosis. Interactions between the epidermal growth factor (EGF) receptor and the HER-2 protein have been described. The aim of this study was to elucidate the effects of EGF on HER-2 expression. In the human ovarian carcinoma cell lines HTB-77, OVCAR-3, 2780, SKOV-6, SKOV-8 and 2774, and the human mammary tumor cell line SKBR-3, total cellular p185HER-2 was determined by an ELISA, whereas the surface p185HER-2 was measured with a living-cell RIA. Stimulation of these cell lines with either EGF (0.1-30 nM) or TGF-alpha (0.1-30 nM) led to a significant reduction in p185HER-2 expression. The effect was more pronounced in cells with normal HER-2 expression. A reduction of mRNA levels for p185HER-2 by EGF was observed in OVCAR-3 cells but not in the over-expressing lines HTB-77 and SKBR-3. Interestingly, the EGF-induced effect was not always associated with growth stimulation and was not correlated with the number of EGF binding sites detected by a radioligand assay. Our data indicate that EGF treatment results in a down-regulation of p185HER-2.
Int J Cancer 1992 Sep 09
PMID:Epidermal growth factor reduces HER-2 protein level in human ovarian carcinoma cells. 135 58

Expression of the c-erbB-2 (neu, HER-2) oncogene is found to be subjected to hormonal and developmental regulation in normal as well as neoplastic mammary cells. We have previously reported that estrogens inhibit c-erbB-2 expression at both the mRNA and protein level in estrogen receptor (ER)-positive, but not in ER-negative, breast cancer cell lines. Reversion of c-erbB-2 inhibition is seen with tamoxifen. The effect on c-erbB-2 expression of several other hormones and factors, which influence mammary cell growth and differentiation, has been studied. Our observations indicate that, in normal and neoplastic mammary cells, c-erbB-2 expression is inversely related to cell proliferation. While estrogens, anti-estrogens and cAMP clearly regulate c-erbB-2 mRNA levels, epidermal growth factor dramatically decreases the c-erbB-2 protein without affecting the level of c-erbB-2 mRNA. Therefore, different signals converging in terms of cell proliferation regulate c-erbB-2 expression by different molecular mechanisms.
J Steroid Biochem Mol Biol 1992 Sep
PMID:Hormonal regulation of c-erbB-2 oncogene expression in breast cancer cells. 135 14

The erbB-2 (HER-2, neu) protooncogene is overexpressed on the surface of about 25% of human breast cancers. It is homologous to epidermal growth factor receptor and a putative growth factor receptor. Overexpression in breast, ovarian and gastric cancers is associated with a worse prognosis. We have recently discovered two ligands for this receptor. They both induce receptor phosphorylation. At low concentrations both induce clonogenic growth of overexpressing cells; at higher concentrations both are growth inhibitory. Both can overcome the inhibitory effects of both monoclonal antibodies directed against the ligand binding site and soluble extracellular domain. These ligands may form an attractive basis for antitumor therapy.
J Steroid Biochem Mol Biol 1992 Sep
PMID:The role of erbB-2 and its ligands in growth control of malignant breast epithelium. 135 15

The neu/erbB-2 protooncogene encodes a transmembrane tyrosine kinase homologous to receptors for polypeptide growth factors. The oncogenic potential of the presumed receptor is released through multiple genetic mechanisms including a point mutation, truncation of non-catalytic sequences and overexpression. The latter mechanism appears to be relevant to human cancers as elevated expression of the neu/erbB-2 gene is frequently observed in solid tumors of various adenocarcinomas. It is therefore conceivable that strategies aimed at the biochemical mechanism of action of the neu/erbB-2 tyrosine kinase may contribute to the treatment of certain human cancers. To this aim we undertook a multiple research approach consisting of the following directions: (i) The neu/erbB-2 ligand--a systematic screening of potential biological sources of the hypothetical hormone molecule, that presumably binds to the neu/erbB-2 protein, resulted in detection of a candidate activity in the medium of certain cultured transformed cells. Partial purification indicated that the factor is a 30-35 kDa glycoprotein. Further studies revealed several biochemical characteristics of the factor that may be helpful for complete purification and structural analysis of this novel hormone. (ii) Signal transduction by neu/erbB-2--using a chimeric receptor approach and various mutants we found that all the oncogenic forms of the neu/erbB-2 are constitutively coupled, both physically and functionally, to a multi-protein complex of signaling molecules. The latter includes the phosphatidylinositol-specific phospholipase C gamma and a phosphatidylinositol kinase. Thus, the metabolism of inositol lipids is probably a major biochemical pathway utilized by the neu/erbB-2 tyrosine kinase. (iii) Tumor inhibitory antibodies--we generated a panel of monoclonal antibodies to the presumed receptor. Surprisingly, some antibodies almost completely inhibited the growth of tumor cells in athymic mice, whereas one antibody significantly accelerated the rate of tumor growth in animals. Interestingly, the inhibitory antibodies conferred a mature phenotype to cultured breast cancer cells, implicating terminal differentiation in tumor retardation.
J Steroid Biochem Mol Biol 1992 Sep
PMID:Signal transduction by the neu/erbB-2 receptor: a potential target for anti-tumor therapy. 135 18

Four residues in the carboxy-terminal domain of human epidermal growth factor (hEGF), glutamate 40, glutamine 43, arginine 45, and aspartate 46 were targeted for site-directed mutagenesis to evaluate their potential role in epidermal growth factor (EGF) receptor-ligand interaction. One or more mutations were generated at each of these sites and the altered recombinant hEGF gene products were purified and evaluated by radioreceptor competition binding assay. Charge-conservative replacement of glutamate 40 with aspartate resulted in a decrease in receptor binding affinity to 30% relative to wild-type hEGF. On the other hand, removal of the electrostatic charge by substitution of glutamate 40 with glutamine or alanine resulted in only a slightly greater decrease in receptor binding to 25% relative receptor affinity. The introduction of a positive charge upon substitution of glutamine 43 with lysine had no effect on receptor binding. The substitution of arginine 45 with lysine also showed no effect on receptor binding, unlike the absolute requirement observed for the arginine side-chain at position 41 [Engler DA, Campion SR, Hauser MR, Cook JS, Niyogi, SK: J Biol Chem 267:2274-2281, 1992]. Subsequent elimination of the positive charge of lysine 45 by reaction with potassium cyanate showed that the electrostatic property of the residue at this site, as well as that at lysine 28 and lysine 48, was not required for receptor-ligand association.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cell Biochem 1992 Sep
PMID:Evaluation of the role of electrostatic residues in human epidermal growth factor by site-directed mutagenesis and chemical modification. 135 99


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