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

Biologically realistic mechanistic models of carcinogenesis by TCDD are composed of equations representing biochemical events leading to altered expression of proteins involved in the response or equations representing the kinetics of proliferation of clones of mutant cells. A biochemically augmented physiological dosimetry model reproduces the observed altered expression of liver proteins in female rats exposed to dioxin. The model suggests that oxidation of estradiol to DNA reactive quinones or semiquinones by CYP1A2 protein induced by TCDD may contribute to an increased mutational rate. It suggests that TCDD-stimulated production of a peptide ligand of the epidermal growth factor (EGF) receptor and subsequent activation of the receptor's tyrosine kinase activity may increase the rate of proliferation of susceptible cells. These calculated quantities can serve as indices of toxicity and can be used to predict tumor incidence as a function of exposure.
Toxicology 1995 Sep 01
PMID:Biochemical mechanisms and cancer risk assessment models for dioxin. 748 48

The amplification and overexpression of the HER-2/neu proto-oncogene, which encodes the tyrosine kinase receptor p185neu, have been observed frequently in tumors from human breast cancer patients and are correlated with poor prognosis. To explore the potential of chemotherapy directed at the tyrosine kinase of p185neu, we have found that emodin (3-methyl-1,6,8-trihydroxyanthraquinone), a tyrosine kinase inhibitor, suppresses autophosphorylation and transphosphorylation activities of HER-2/neu tyrosine kinase, resulting in tyrosine hypophosphorylation of p185neu in HER-2/neu-overexpressing breast cancer cells. Emodin, at a 40-microM concentration, which repressed tyrosine kinase of p185neu, efficiently inhibited both anchorage-dependent and anchorage-independent growth of HER-2/neu-overexpressing breast cancer cells. However, the inhibition was much less effective for those cells expressing basal levels of p185neu under the same conditions. Emodin also induced differentiation of HER-2/neu-overexpressing breast cancer cells by exhibiting a morphological maturation property of large lacy nuclei surrounded by sizable flat cytoplasm and by showing a measurable production of large lipid droplets, which is a marker of mature breast cells. Therefore, our results indicate that emodin inhibits HER-2/neu tyrosine kinase activity and preferentially suppresses growth and induces differentiation of HER-2/neu-overexpressing cancer cells. These results may have chemotherapeutic implications for using emodin to target HER-2/neu-overexpressing cancer cells.
Cancer Res 1995 Sep 01
PMID:Suppressed transformation and induced differentiation of HER-2/neu-overexpressing breast cancer cells by emodin. 754 19

Mutation and overexpression of p53 occurs in 20-40% of breast cancers and has been shown to be an independent prognostic indicator. Recently we have demonstrated prostate-specific antigen (PSA) expression in breast tumours to be suggestive of favourable prognosis, but quantitative relationships between PSA and p53, and between these and other prognostic factors in breast cancer, have not been investigated. Time-resolved immunofluorometric procedures were used to quantify both p53 protein and PSA in 200 breast tumour extracts, which were also assayed for oestrogen (ER) and progesterone receptors (PGR), epidermal growth factor receptors (EGFR), cathepsin D and HER-2/neu, and characterised for S-phase fraction and DNA ploidy. Weak Spearman correlations were found between p53 and ER (r = - 0.18, P = 0.010), PGR (r = - 0.15, P = 0.0385) and S-phase fraction (r = 0.17, P = 0.016), while PSA was correlated only with PGR (r = 0.16, P = 0.025). Wilcoxon rank sum analysis revealed that levels of ER (P = 0.0001), PGR (P = 0.0001), S-phase fraction (P = 0.0001) and EGFR (P = 0.0014) differed significantly between the two groups categorised as p53 negative or p53 positive. Tumours classified as PSA negative or PSA positive were found to differ with respect to PGR (P = 0.0091) and S-phase fraction (P = 0.011) in a similar analysis. Contingency tables indicated significant negative associations between the status of p53 and that of ER (P = 0.003) and PGR (P = 0.001) and between PSA and S-phase fraction (P = 0.012), and positive associations between p53 and EGFR (P = 0.017), HER-2/neu (P = 0.008), S-phase fraction (P = 0.001) and aneuploidy (P = 0.007), and between PSA and both ER (P = 0.061) and PGR (P = 0.010). No significant associations were found between p53 and PSA. Our results demonstrate that the presence of p53 in breast tumours relates to several other variables which are suspected to predict aggressive tumour phenotypes and that the presence of PSA relates to variables associated with good prognosis.
Br J Cancer 1995 Sep
PMID:Immunofluorometric analysis of p53 protein and prostate-specific antigen in breast tumours and their association with other prognostic indicators. 754 16

Fifty-three solid and 33 fine-needle aspirate (FNA) samples (20 paired) of human breast carcinomas were examined by flow cytometry. Experiments were conducted to assess whether FNA samples were phenotypically representative of the solid tumour. Quantification of oestrogen receptor (ER), epidermal growth factor receptor (EGFR), c-erbB-2 receptor levels and ploidy were examined on the total and cytokeratin-positive cell populations. The absolute number of molecules of cytokeratin per cell expressed on the FNA (n = 33) and solid tumour (n = 53) samples showed no significant difference, but, on a proportional basis, there was a significant difference between the two samples (P = 0.004), with lower expression exhibited by the FNAs. Examination of paired data showed no significant difference in the percentage of cytokeratin-positive cells (P = 0.51) or in the number of cytokeratin molecules expressed (P = 0.25). While the correlation for ER expression between paired tumour and FNA samples in the absence of cytokeratin gating was P = 0.06, r2 = 0.18, clear correlation was shown when a cytokeratin gate was used (P = 0.005, r2 = 0.4). Repeating this experiment for EGFR, it was found that no correlation was seen between FNA and solid tumour (P = 0.2, r2 = 0.14) in ungated populations, but use of the cytokeratin gate improved the correlation (P = 0.05, r2 = 0.3). A similar finding was seen with c-erbB-2 expression (P = 0.2, r2 = 0.1) without cytokeratin gating and when it was employed (P = 0.05, r2 = 0.4). Ploidy data showed concordance in 18/20 cases. Three cases of aneuploidy were missed by FNA, and this was because of an insufficient number of cells for analysis. The presented data suggest that FNAs are representative of solid tumours and may be useful for measuring receptor levels on clinical material when cytokeratin gating is used. However, observation by light microscopy is still necessary to confirm the presence of tumour cells in FNAs subjected to flow cytometry.
Br J Cancer 1995 Sep
PMID:Are fine-needle breast aspirates representative of the underlying solid tumour? A comparison of receptor levels, ploidy and the influence of cytokeratin gates. 754 18

Quantification of c-erbB-2 and its relationship with other prognostic markers using flow cytometry has been examined. In this study a level for c-erbB-2 expression above which tumours are classified as positive by flow cytometry has been determined by employment of positive cut-off threshold levels. c-erbB-2 expression by both flow cytometry and immunohistochemistry was studied using the monoclonal antibody NCL-CBII. The relationship of c-erbB-2 quantification by flow cytometry was then compared with ploidy, axillary node status, tumour size and grade. Increased c-erbB-2 expression was seen using flow cytometry. Correlation between immunohistochemistry and flow-cytometry methods just failed to reach significance (P = 0.06). Immunohistochemistry revealed a significant relationship between c-erbB-2 expression and aneuploidy (P = 0.04). Cytokeratin-positive cells from 110 samples obtained from patients with breast cancer were assayed for DNA content and c-erbB-2 expression by flow cytometry. No correlation was seen between these parameters upon application of Mann Whitney analysis. However, examination of fluorescence thresholds showed a positive correlation between grade and c-erbB-2 expression at a level of more than 3200 molecules (P < or = 0.03). At the level of 3600 molecules significance was increased (P = 0.004). These levels equated with between 15% and 19% of the samples being classified as c-erbB-2-positive. Application of these cut-off points showed no correlation between c-erbB-2 expression and ploidy, tumour size or axillary node status. Comparison of ploidy and grade showed a significant association (P = 0.0015), increased grade correlating with aneuploidy.
Cancer Immunol Immunother 1995 Sep
PMID:The relationship between flow-cytometric and immunohistochemically detected c-erbB-2 expression, grade and DNA ploidy in breast cancer. 755 81

The erbB-2 oncogene encodes a transmembrane protein tyrosine kinase which plays a pivotal role in signal transduction and has been implicated when overexpressed in breast, ovarian, and gastric cancers. Naturally occurring benzoquinoid ansamycin antibiotics herbimycin A, geldanamycin (GDM), and dihydrogeldanamycin were found to potently deplete p185, the erbB-2 oncoprotein, in human breast cancer SKBR-3 cells in culture. Chemistry efforts to modify selectively the quinoid moiety of GDM afforded derivatives with greater potency in vitro and in vivo. Analogs demonstrated inhibition of p185 phosphotyrosine in cell culture and in vivo after systemic drug administration to nu/nu nude mice bearing Fisher rat embryo cells transfected with human erbB-2 (FRE/erbB-2). Specifically, dosed intraperitoneally at 100 mg/kg, 17-(allylamino)-17-demethoxygeldanamycin and other 17-amino analogs were effective at reducing p185 phosphotyrosine in subcutaneous flank FRE/erbB-2 tumors. Modifications to the 17-19-positions of the quinone ring revealed a broad structure-activity relationship in vitro.
J Med Chem 1995 Sep 15
PMID:Inhibition of the oncogene product p185erbB-2 in vitro and in vivo by geldanamycin and dihydrogeldanamycin derivatives. 756 11

Overexpression of the erbB-2 oncogene has been linked to poor prognosis in breast, ovarian, and gastric cancers. Naturally occurring benzoquinoid ansamycin antibiotics herbimycin A, geldanamycin (GDM), and dihydrogeldanamycin were found to potently deplete p185, the erbB-2 oncoprotein, in human breast cancer SKBR-3 cells in culture. Chemistry efforts to modify selectively the ansa ring of GDM afforded derivatives with greater potency in vitro and in vivo. Analogs demonstrated inhibition of p185 phosphotyrosine in cell culture and in vivo after systemic drug administration to nu/nu nude mice bearing Fisher rat embryo cells transfected with human erbB-2. Functional group modification in the ansa ring was performed stereoselectively and regiospecifically without the need for protection strategies. Essential functional groups that were required for anti-erbB-2 activity were the 7-carbamate and the 2,3-double bond. Modification of the functional groups at the other positions was permitted. Structure-activity relationships are described for 1-5-, 7-9-, 11-, 15-, and 22-substituted geldanamycins.
J Med Chem 1995 Sep 15
PMID:erbB-2 oncogene inhibition by geldanamycin derivatives: synthesis, mechanism of action, and structure-activity relationships. 756 12

To determine whether LH receptor rotational diffusion is similar in closely related species, we compared the rotational correlation times of LH receptors on bovine CL membranes with those of LH receptors on sheep small luteal cells and luteal cell plasma membranes using time-resolved phosphorescence anisotropy techniques. After binding of erythrosin isothiocyanate (ErITC)-derived bovine LH (bLH), ErITC-ovine LH (oLH), or ErITC-hCG, there was no difference in the initial and final anisotropy at 4 degrees C, 15 degrees C, 25 degrees C, and 37 degrees C, indicating that the bLH receptor was rotationally immobile on the time scale of our experiments. On these same membrane preparations, the epidermal growth factor (EGF) receptor occupied by ErITC-murine EGF exhibited temperature-dependent rotational correlation times of 80 +/- 5 microseconds, 111 +/- 7 microseconds, 254 +/- 4 microseconds, and > 1000 microseconds at 4 degrees C, 15 degrees C, 25 degrees C, and 37 degrees C, respectively. Slower rotational times for EGF receptor observed at higher temperatures suggested the occurrence of temperature-dependent receptor aggregation. Like the bLH receptor, the oLH receptor on intact cells and on CL plasma membranes was rotationally immobile on the time scale of our experiments when occupied by ErITC-hCG. However, the oLH-occupied receptors on small luteal cells and on luteal cell membranes had comparable rotational correlation times at 37 degrees C. These results suggest that bLH receptors are present in large, rotationally immobile structures, whereas the receptor-containing structure formed on ovine luteal cells depends on whether that receptor is occupied by hCG or oLH. Also, despite the similarities between reproductive function in these species, the LH-occupied receptor appears to be organized differently in the plasma membranes of these hormone-responsive luteal cells.
Biol Reprod 1995 Sep
PMID:Rotational dynamics of luteinizing hormone receptors on bovine and ovine luteal cell plasma membranes. 757 89

The expression of amphiregulin (AR), heregulin (HRG), and cripto-1 (CR-1) mRNA transcripts was assessed in 60 human primary breast carcinoma. AR and HRG transcripts were expressed respectively in 58% and 25% of the carcinomas as measured by Northern blot analysis. CR-1 mRNA was found in 77% of the carcinomas using Reverse Transcriptase-PCR analysis. Coexpression of two or three of these peptides was observed in several specimens. There was no significant association between AR, HRG, and CR-1 expression and nodal status, EGF receptor, or c-erbB-2 protooncogene expression in these tumors. However, a significant association between AR expression and estrogen receptor positivity was observed.
Breast Cancer Res Treat 1995 Sep
PMID:Expression of messenger RNA for amphiregulin, heregulin, and cripto-1, three new members of the epidermal growth factor family, in human breast carcinomas. 757

A homogeneous assay method based on the long-lived fluorescence of rare earth cryptates and amplification by nonradiative energy transfer has been developed for immunoassays. The principles of the assay allow a double discrimination of the emitted signal through spectral and temporal selectivity. The cage structure of the complex, ion pairing around europium, as well as double-wavelength detection, fully shield the assay from perturbations of media. Events based on short-range interactions involving biomolecules are of tremendous importance in many domains of biology, either for analytical purposes or for molecular mechanism studies. Therefore, the principles and the reagents used to devise this homogeneous assay were adapted to various models representative of molecular and cellular processes and were chosen from the signaling pathways involved in cellular communication and expression: epidermal growth factor (EGF) receptor-ligand interaction, EGF receptor kinase activity, Jun/Fos protein-protein interaction, and DNA hybridization. Evaluation of the homogeneous assays yielded results compatible with those from comparison assays and demonstrates the versatility and wide range of applicability of this methodology.
Clin Chem 1995 Sep
PMID:Probing molecular interactions with homogeneous techniques based on rare earth cryptates and fluorescence energy transfer. 765 55


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