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)

The endocytosis of gp185erbB-2 was studied using chimeric receptors in which the intracellular domain of erbB-2, or subdomins thereof, was substituted for the corresponding regions of the epidermal growth factor (EGF) receptor. Chimeric and wild-type EGF or erbB-2 receptors were expressed in mouse NIH3T3 or NR6 fibroblasts and in a human mammary adenocarcinoma cell line, MDAMB-134. The rate of EGF-induced internalization for the chimera consisting of the extracellular EGF receptor domain and intracellular erbB-2 domain was reduced three- to fourfold compared with the wild-type EGF receptor. The low rate of internalization of the chimeric receptor resulted in impaired down-regulation and degradation of the receptor. Substitution of the carboxyl terminus of erbB-2 for the corresponding region of the EGF receptor caused a similar decrease of receptor endocytosis, whereas substitution of the erbB-2 tyrosine kinase domain did not affect internalization and down-regulation. Since the tyrosine kinase of the internalization-defective chimeric receptors could be activated by EGF, kinase activity and autophosphorylation of erbB-2 do not appear to be sufficient for a maximum rapid internalization of the chimeric receptors. These results suggest that the carboxyl terminus of erbB-2 either does not possess all the signals required for the rapid internalization or contains an inhibitory signal for rapid internalization.
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PMID:The carboxyl terminus of epidermal growth factor receptor/erbB-2 chimerae is internalization impaired. 810 39

We have previously described anti-epidermal growth factor (EGF) receptor monoclonal antibodies (MAbs) which can block binding of transforming growth factor alpha (TGF-alpha) and EGF to receptors and inhibit activation of receptor tyrosine kinase. Studies with these MAbs involving cell cultures and nude mouse xenografts demonstrated their capacity to inhibit the growth of a variety of tumor cell lines, which express EGF receptors and TGF-alpha and appear to depend upon receptor activation for cell proliferation. To explore the mechanism(s) by which anti-EGF receptor 225 MAb inhibits cell proliferation, we have compared the activity of native 225 MAb with the response to bivalent 225 F(ab')2 and monovalent 225 Fab' fragments. Both native 225 MAb and its fragments could inhibit the binding of 125I-EGF to EGF receptors. Scatchard analysis revealed that the Kd of 225 F(ab')2 is comparable to that of 225 MAb (1 nM), whereas the Kd of 225 Fab' is 5 nM. Both bivalent 225 MAb and 225 F(ab')2 and monovalent 225 Fab' were able to completely inhibit TGF-alpha-induced EGF receptor tyrosine kinase activation, as assayed by autophosphorylation of tyrosine residues of EGF receptors on MCF10A nonmalignant human mammary cells, MDA468 human breast adenocarcinoma cells, and A431 human vulvar squamous carcinoma cells. The bivalent forms of MAb could inhibit proliferation stimulated by endogenous (autocrine) TGF-alpha in cultures of these three cell lines. They also blocked growth stimulation by added exogenous TGF-alpha in cultures of MCF10A cells and the growth-inhibitory effect of exogenous TGF-alpha upon MDA468 and A431 cell cultures. Monovalent 225 Fab' had weaker inhibitory effects upon the proliferation of these cell lines. To determine whether the in vivo antiproliferative activity of anti-EGF receptor MAb can occur without the participation of the Fc portion of MAb, the capacities of 225 F(ab')2 and native 225 MAb to inhibit growth of s.c. A431 cell xenografts were compared. Equimolar amounts of either 225 MAb or 225 F(ab')2 were administered at intervals equivalent to the half-lives of the molecules, to attempt to maintain comparable plasma levels. Both 225 MAb and 225 F(ab')2 inhibited A431 cell xenograft growth in a dose-dependent manner, with a more sustained response in the case of the intact antibody.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Blockade of epidermal growth factor receptor function by bivalent and monovalent fragments of 225 anti-epidermal growth factor receptor monoclonal antibodies. 836 27

This review examines methods of assessing the prognosis of uterine tumors published in the past year. Evaluation of mitosis counts has shown that mitotically active leiomyomas without cytologic atypia follow a benign course; furthermore, the mitotic index does not differentiate endometrial hyperplasia from adenocarcinoma. 'Vascular invasion-associated changes' (VIAC) have been identified as a new prognostic factor for stage 1 endometrial adenocarcinoma. HER-2/neu oncogene expression is also a major prognostic factor in endometrial carcinoma, but positive peritoneal cytology influences survival only in the presence of extrauterine disease. Frozen-section diagnosis and curettings findings at the time of surgery identify poor prognostic factors, allowing limited surgery in patients without poor prognostic indicators. Finally, DNA ploidy as determined by flow cytometry was of prognostic value in uterine sarcomas in one study but not in another when endometrial stromal sarcomas were analysed separately.
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PMID:Pathological findings and prognosis from uterine malignancy. 840 44

Proliferating cell nuclear antigen (PCNA) expression was studied by immunohistochemistry on paraffin-embedded sections of 293 primary colorectal adenocarcinomas and 56 corresponding lymph node metastases. PCNA-positive expression was detected in <25% of tumour cells in 172 (59%) cases and in > 25% in 121 (41%) cases. PCNA accumulation was related to over-expression of c-erbB-2 and p53 and tended to be increased in cases with ras over-expression. PCNA expression was identical in primary and corresponding metastases. No significant relationship was observed between PCNA expression and prognosis and other clinico-pathological variables, including grade of differentiation, growth pattern, Dukes' stage, site, age or sex. We conclude that PCNA expression may be related to alterations of oncoproteins but that PCNA itself could not provide additional information for the development of metastasis and prognosis in colorectal adenocarcinoma.
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PMID:Proliferating cell nuclear antigen (PCNA) in relation to ras, c-erbB-2,p53, clinico-pathological variables and prognosis in colorectal adenocarcinoma. 860 60

Differences in the immunohistochemical expression of Cathepsin D, C-erbB-2 protein (p185), and growth fraction (MIB-1) in glandular and squamous epithelium in adenocarcinoma of endometrioid subtype were studied together with Cathepsin D in macrophages. The findings were correlated with conventional prognostic parameters. A search for human papilloma virus (HPV) (probes 6/11, 16/18, and 31/33/51) by in situ hybridization was also performed. Formalin-fixed and paraffin-embedded tissues from 61 adenocarcinomas with > 10% squamous epithelium were studied. MIB-1 was very low in squamous epithelium, no correlation was found between MIB-1 in squamous and glandular epithelium, and only the glandular epithelium correlated with depth of invasion and stage, indicating that glands are most important with regard to prognosis. Cathepsin D expression in macrophages was significantly increased in advanced stage and may be of prognostic value, but more studies on tissue sections are needed to evaluate the relationship between its expression in tumor cells and other cells. p185 showed no value as a prognosticator. Finally, our study found HPV infrequently in endometrial carcinomas.
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PMID:Endometrial adenocarcinoma of endometrioid subtype with squamous differentiation: an immunohistochemical study of MIB-1 (ki-67 paraffin), cathepsin D, and C-erbB-2 protein (p185). 860 74

Although several morphological and molecular genetic studies have implicated various grades of pancreatic duct hyperplasia as precursor lesions to infiltrating pancreatic adenocarcinoma, the identity of preinvasive pancreatic neoplasms remains controversial. In the present study, the authors examined the expression of the epidermal growth factor receptor homologue, HER-2/neu (c-erbB-2), in pancreatic duct lesions adjacent to infiltrating pancreas cancers in a series of 19 cases of pancreatic duct adenocarcinoma. HER-2/neu expression was examined because it has been identified in a proportion of infiltrating pancreas cancers and because it may provide early neoplasms with a growth advantage over adjacent nonneoplastic epithelium. In normal pancreatic ducts and ductules, HER-2/neu expression was absent in all but one case. By contrast, HER-2/neu was expressed in 82% (P = .008 vs normal ) of ducts with flat mucinous hyperplasia, 86% (P = .03 vs normal) of ducts with papillary mucinous hyperplasia without atypia, 92% (P = .001 vs normal) of ducts with atypical papillary mucinous hyperplasia, and all specimens with carcinoma in situ. HER-2/neu expression was observed in 69% (P = .002 vs normal) of the moderately differentiated infiltrating carcinomas and none of the poorly differentiated infiltrating carcinomas. These data establish HER-2/neu as a potential mediator of growth factor-related signal transduction in pancreatic duct lesions, and provide additional support for the hypothesis that lesions formerly regarded as various grades of hyperplasia instead may represent intraepithelial neoplasms with the potential for subsequent invasion and metastasis.
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PMID:Immunohistochemical evaluation of HER-2/neu expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasms. 861 52

Activation of the cyclin dependent kinases (CDK4/CDK6 and CDK2) is required for G1 phase progression and entry into S-phase. The activation of these kinases is regulated by checkpoints that monitor environmental and intracellular conditions. Progression into S-phase is controlled, in part, by the availability of growth factors, and we have investigated the relationship between growth factor availability and the activation of the CDK kinases. Blocking activation of epidermal growth factor (EGF) receptor tyrosine kinase with anti-EGF receptor monoclonal antibody (mAb) 225 induces G1 phase cell cycle arrest in DiFi human colon adenocarcinoma cells. When DiFi cells are treated with mAb 225 for 24 h, we observe marked decreases in the activities of CDK2 kinase and cyclin E-associated CDK kinase which are not accompanied by reduced levels of cyclin E and CDK2 proteins. However, the amount of cyclin/CDK kinase inhibitor p27KIP1 increases in the mAb-treated cells and p27KIP1 is bound to CDK2 in increasing amounts. Immunodepletion of p27KIP1 removes an inhibitory activity from lysates of mAb-treated cells: the immunodepleted and heated lysates lose the capacity to inhibit cyclin E/CDK2 activity in an in vitro assay. The results suggest that G1 arrest in the cell cycle induced by EGF receptor blockade involves p27KIP1.
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PMID:Involvement of p27KIP1 in G1 arrest mediated by an anti-epidermal growth factor receptor monoclonal antibody. 862 55

Human parotid tumors were evaluated for the activation of the phosphotyrosine signaling pathway by Western blot, enzyme activity assay, and reverse transcriptase-polymerase chain reaction. Warthin's tumor and mucoepidermoid carcinomas had the greatest level of tyrosine phosphorylated proteins identified in plasma membrane fractions. These tumors, along with pleomorphic adenocarcinoma, showed high levels of membrane expression of the tyrosine kinase receptor, c-erbB-2, and phosphatidylinositol-3-kinase. Expression of the epidermal growth factor receptor was confined to normal tissue. The level of mRNA for c-erb was elevated only in mucoepidermoid carcinomas. Messenger RNA levels for ras were unchanged from control levels in all tumors, while the level of src mRNA was higher in the tumor samples than the normal parotid tissue. The activities of several signal transduction kinases, including protein kinase A and C were elevated in tumor tissue (7.7- to 18.9- and 0.4- to 3.7-fold higher, respectively), relative to surrounding normal tissue. While the level of glandular amylase was reduced (22%-0% of normal levels) in the tumor tissue, epidermal growth factor (EGF) and transforming growth factor-alpha (TGFalpha) content was dramatically higher in the neoplastic tissue (10- to 170-fold and 4.6- to 6.0-fold, respectively). These results suggest that with the presence of elevated levels of EGF, TGFalpha, and the oncoprotein receptor c-erbB-2 in the membrane of parotid tumors, cell proliferation and activation of the phosphotyrosine signal transduction pathway may involve autocrine stimulation through the expression of high levels of growth factor and receptor in the same tissue.
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PMID:Alterations in the level of phosphotyrosine signal transduction constituents in human parotid tumors. 863 6

A series of 19 cases of carcinoma ex-pleomorphic adenoma was studied for the immuno-expression of c-erbB-2 oncoprotein. Twelve tumours showed a malignant component with only one histological type; in the remaining seven there was co-existence of areas of various carcinoma types, adenocarcinoma NOS being the most frequent. Membranous c-erbB-2 reactivity was found in 21.1% of the cases, all corresponding to high-grade adenocarcinomatous areas. The low-grade carcinoma types that formed the malignant mixed tumours components were negative. Benign pleomorphic adenoma areas, either adjacent or intermingled with carcinomatous areas, were also consistently negative, proving that c-erbB-2 accumulation is associated with the acquisition of the malignant phenotype. The finding of a preferential association between c-erbB-2 overexpression and high-grade malignant mixed tumour may indicate prognostic implications for the oncogene protein and may also be indicative of its specific relationship with the putative pathway of malignant transformation in pleomorphic adenomas.
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PMID:Immunohistochemical study of c-erbB-2 expression in carcinoma ex-pleomorphic adenoma. 872 44

The aim of this preliminary study was to evaluate retrospectively sestamibi scintigraphy in relation to the presence of the 170-kDa P-glycoprotein (Pgp), which represents an expression of multidrug resistance in patients with primary breast cancer. Fifteen women (age range 37-76 years) were referred for technetium-99m sestamibi scintigraphy because of suspicious breast lesions detected by mammography and ultrasonography, and subsequently assessed by fine-needle aspiration. Scintigraphy was performed 30 min following the injection of 500 MBq 99mTc-sestamibi. Three planar anterior and oblique images were obtained with the patient in the supine position. Excised tumours were assessed for cytosolic CA 15.3, oestrogen (OR) and progesterone (PR) receptors and c-erb B2 neu oncogene. Pathology revealed that only 13 of the 15 patients had malignant tumours. The two benign tumours were sestamibi-negative and Pgp-positive. Sestamibi scintigraphy was positive in 10 of the 13 malignant lesions (including nine of ten infiltrating ductal carcinomas). Two of the three lesions with false-negative scintigraphy were Pgp-negative; in one of these cases histology revealed an invasive lobular carcinoma and in the other, mucinous adenocarcinoma. The third false-negative lesion was a Pgp-positive infiltrating ductal carcinoma which was c-erb B2 neu-negative but CA 15.3-, OR- and PR-positive. This preliminary study confirms that the resistance to chemotherapy which may occur in patients with primary breast cancer can be a cause of negative sestamibi scintigraphy.
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PMID:Primary breast cancer imaging with technetium-99m sestamibi and its relation with P-glycoprotein overexpression. 875 90


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