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)

Human endometrial adenocarcinoma cells (Ishikawa line) constitutively express c-erbB2 coded oncoprotein p185erbB2 (p185) which is believed to be an orphan receptor for an unknown growth factor. Since we have shown that expression of p185 in primary lesions of endometrial cancer correlates well with high frequency of lymph node++ metastases and that the metastatic cells in the nodes strongly expressed p185, the role of the oncoprotein in processes of metastases was studied. Culturing the cells in the presence of 15% FCS and with monoclonal antibody to the extracellular domain of p185 (CB-1) inhibited cell growth and attenuated p185 expression on Western blotting, whereas no change occurred with the control antibody. Cells cultured without FCS achieved only approximately 1/3 growth compared to cells with FCS, and further suppression of growth was observed after adding CB-1. When cells were cultured on human term amnion, basement membrane invasion with p185 expression was observed. In nude mice, intraperitoneal seeding resulted in implant formation which was also associated with positive p185 as well as cyclin immunohistochemistry. In the two experiments, treatment of cells with CB-1 inhibited invasion or implant formation. The present study suggests that a signal through p185 receptor molecules acts as a trigger for early proliferation, and interaction with the host may enhance up-regulation of p185.
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PMID:[Role of p185c-erbB2 in endometrial cancer growth in vitro]. 135 38

Cytogeneticists first proposed that the karyotypic abnormalities identified on chromosomes 1, 3, 6, 11, 13, 16, 17, and 18 supported a genetic basis for breast cancer. Such abnormal banding patterns, however, may represent either loss-of-function or gain-of-function molecular events. RFLP analyses have since confirmed that 20-60% of primary and spontaneous human breast tumors exhibit allelic losses on these same chromosomes, although the exact genes involved at these chromosomal sites remain largely unknown. Knowledge gained about the Rb-1 and p53 tumor suppressor genes at 13q14 and 17p13 in breast and other human tumors supports the paradigm that for any chromosomal locus, allelic loss associated with a mutation in the remaining tumor allele signifies an involved tumor suppressor gene. Given this paradigm, there are nearly a dozen putative breast tumor suppressor genes under active investigation, with most investigators now focusing on various chromosome 17 loci. Among the known proto-oncogenes found activated in breast cancer, amplification of c-erbB-2 at 17q21 is the most widely studied and clinically significant gain-of-function event uncovered to date, occurring in about 20% of all primary breast tumors. The involvement of this overexpressed membrane receptor has engendered interest in related tyrosine kinase receptors, such as EGFR, IR, and IGF-I-R, as well as their respective ligands, which may be overexpressed in a greater fraction of tumors, contributing to the autocrine and paracrine regulation of breast cancer growth and metastasis. New attention is being given to the potentially oncogenic function of structurally altered nuclear transactivating steroid hormone receptors, such as ER, whose overexpression has long been used to determine endocrine therapy and prognosis for individual breast cancer patients. While c-myc was one of the first known proto-oncogenes to be found amplified and overexpressed in human breast cancers, the actual incidence and clinical significance of its activation remain disputed and in need of further study. Lastly, we can expect greater clarification about the importance of various 11q13 genes found coamplified in nearly 20% of primary breast cancers, and pursuit into the intriguing possibility that a cyclin-encoding gene represents the overexpressed locus of real interest in this amplicon. Virtually all of these important genetic abnormalities identified thus far are associated with but not restricted to human breast cancers. The absence of identifiable molecular defects relating to the tissue specificity of this malignancy must be considered a substantial gap in our basic understanding of breast carcinogenesis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Activated oncogenes and putative tumor suppressor genes involved in human breast cancers. 136 56

It is important to know the proliferating ability and the malignant potential of tumor tissues. We have examined the expression of PCNA/cyclin, p53 and C-erbB-2 in transitional cell carcinoma of the human urinary bladder by an immunohistochemical method, and compared the results with the histological grade, stage and survival rate. Immunohistochemical studies, using monoclonal and polyclonal antibodies, on these proteins were performed with formaline fixed-paraffin sections of tumor tissue from 40 patients with bladder cancer. Generally, a higher grade and higher stage tumors expressed PCNA/cyclin, p53 and C-erbB-2 with a greater frequency than the tumors with a lower grade and lower stage and strongly stained cases had a lower survival rate than weakly stained cases. These findings suggest that the detection of each antigen is useful for estimating the malignant potential of transitional cell carcinoma as the adjuvant studies, because of its applicability to paraffin-embedded tissue sections and its simple, rapid technique.
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PMID:[Expression of PCNA/cyclin, p53, C-erbB-2 versus histological grade in transitional cell carcinoma of urinary bladder]. 778 54

Transforming growth factor beta (TGF beta) acts on epithelial thyroid cells, negatively controlling their proliferation and functions. The effects of TGF beta on epithelial rat thyroid cells (FRTL-5) and on two TGF beta-resistant rat thyroid cell clones (FRTL-5H2 and FRTL-R) were investigated. FRTL-5H2 represents a rat thyroid cell clone overexpressing active erbB-2 oncogene, recently obtained after FRTL-5 cell infection with a retrovirus vector carrying the erbB-2 human oncogene (G. Mincione et al., Cancer Res., 53: 5548-5553, 1993). FRTL-R is a FRTL-5 subclone spontaneously isolated after long term in culture. FRTL-5H2 and FRTL-R cell clones were stimulated by TGF beta at the same concentration of 5 ng/ml that induced 70% inhibition of [3H]thymidine incorporation in control FRTL-5 thyroid cells. Nuclear events regulated by TGF beta, such as cyclin and cyclin-dependent kinase gene expression, were then analyzed. In FRTL-5 cells, TGF beta was found to reduce the expression of cdk2 and cyclin A genes; the same treatment did not modify nuclear gene expression in the resistant cell clones. TGF beta is known to reduce iodide uptake in thyroid cells; in both FRTL-5H2 and FRTL-R cells, TGF beta was found to inhibit the thyrotropin-induced iodide uptake. Thus, thyroid cell clones, resistant to the growth-inhibitory activity of TGF beta, were sensitive to TGF beta inhibition of iodide incorporation, suggesting that TGF beta activates divergent signaling pathways in these cells, separately controlling cell proliferation and differentiation parameters. Studies on TGF beta receptors showed similar amounts of TGF beta-binding species on FRTL-5 cells and TGF beta-resistant clones, while 125I-labeled TGF beta cross-linking experiments revealed differences; thus, the TGF beta-resistant cells showed a 40% decrease in the amount of labeled type II TGF beta receptor on the cell surface. However, this different pattern of TGF beta receptors cannot totally account for the shown TGF beta resistance to growth inhibition that might also be due to perturbation in signaling pathways.
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PMID:Epithelial rat thyroid cell clones, escaping from transforming growth factor beta negative growth control, are still inhibited by this factor in the ability to trap iodide. 779 96

Gene amplification in stomach and oesophageal cancers was reviewed. In stomach cancers, two receptor type tyrosine kinases, c-erbB-2 and K-sam, are frequently amplified and overexpressed. c-erbB-2 seems to be preferentially amplified in well-differentiated, and K-sam in poorly-differentiated, gastric adenocarcinomas. 11q13 genes are amplified in about 50% of the oesophageal cancers. These genes include hst-1, int-2 and cyclin D/prad1, all of which are mapped to chromosome 11 at band q13. Although hst-1 and int-2 are usually not expressed despite amplification, elevated transcription of the cyclin D gene is accompanied by its amplification, suggesting a role of a G1 cyclin in oesophageal carcinogenesis.
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PMID:Amplified genes in cancer in upper digestive tract. 809 12

The authors attempted to estimate the relationship between three biological parameters (nuclear DNA content, PCNA (proliferating cell nuclear antigen)/cyclin, HER-2/neu oncoprotein) and lymph node metastasis. We evaluated 37 breast cancers which were less than 2 cm in maximum dimension. Quantitative analysis was performed using a CAS 200 Image Analysis System, after Feulgen staining and immunochemical staining using anti-PCNA/cyclin monoclonal antibody and anti-HER-2/neu oncoprotein polyclonal antibody. In lymph node-negative cases 20.0% were aneuploid, while in lymph node-positive cases 58.8% were aneuploid. A total of 20.0% lymph node-negative cases were in the high proliferation group, as opposed to 52.9% of lymph node-positive cases. This analysis revealed a significant relationship between cell proliferation and lymph node metastasis. Analysis of the expression of HER-2/neu oncoprotein revealed no significant relationship between overexpression of HER-2/neu oncoprotein and lymph node metastasis, but the expression of HER-2/neu oncoprotein was significantly related to a shorter relapse-free survival.
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PMID:[Quantitative cytochemical analysis of T1 breast cancer]. 809 99

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

In the medical literature there are frequently conflicting reports on the utility of biological tumour markers available in the clinical management of breast cancer. In this review we analyse current information on the relationships between the most widely investigated breast cancer biological markers including oestrogen and progesterone receptors, p53, Bcl-2, c-erbB-2, cyclin expression, proliferative activity, DNA ploidy and the urokinase plasminogen activation system, as well as their relevance to prognosis and response to clinical treatment. By biological prognostic indicator, we mean a marker that correlates with survival and disease-free survival; the term predictor marker indicates a marker that is capable of predicting tumour sensitivity or resistance to various therapies. Similarly to other authors' experiences, our analysis suggests that oestrogen receptors are weak prognostic indicators and good predictors of response to endocrine therapy. Furthermore, there are consistent data suggesting that proliferation indices are good indicators of prognosis, and that they are directly related to response to chemotherapy and closely related to response to hormonotherapy. On the contrary, there is no evidence or conflicting data for all of the other biological markers. These should be considered in the context of randomized trials in order to precisely define their prognostic and predictive roles. p53 and c-erbB-2 seem to be the most promising factors, but their use in routine practice still needs validation.
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PMID:Prognosis and prediction of response in breast cancer: the current role of the main biological markers. 985 25

There is at present, much optimism about the possibility of finding selective anticancer drugs that will eliminate the cytotoxic side effects associated with conventional cancer chemotherapy. This hope is based on uncovering many novel molecular targets that are 'cancer-specific', which will allow the targeting of cancer cells while normal cells are spared. Thus far, encouraging results have been obtained with several of these novel agents at the preclinical level, and clinical trials have begun. These targets are involved at one level or more in tumor biology, including tumor cell proliferation, angiogenesis and metastasis. Novel targets for which advances are being made include the following: growth factor receptor tyrosine kinases such as the epidermal growth factor receptor and HER-2/neu (proliferation); the vascular endothelial growth factor receptor and the basic fibroblast growth factor receptor (angiogenesis); the oncogenic GTP-binding protein Ras (especially agents targeting Ras farnesylation, farnesyltransferase inhibitors) (proliferation); protein kinase C (proliferation and drug resistance); cyclin-dependent kinases (proliferation); and matrix metalloproteinases and angiogenin (angiogenesis and metastasis). Less explored, but potentially useful targets include the receptor tyrosine kinase platelet-derived growth factor receptor, mitogen-activated protein kinase cascade oncogenes such as Raf-1 and mitogen-activated protein kinase kinase, cell adhesion molecules such as integrins, anti-apoptosis proteins such as Bcl-2, MDM2 and survivin, and the cell life-span target telomerase.
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PMID:Novel anticancer drug discovery. 1041 54

Flavopiridol is a flavone that inhibits several cyclin-dependent kinases and exhibits potent growth-inhibitory activity against a number of human tumor cell lines, both in vitro and when grown as xenografts in mice. It is presently being investigated as a novel antineoplastic agent in the primary screen conducted by the Developmental Therapeutics Program, National Cancer Institute. Because breast cancer is the most common cancer and second leading cause of cancer-related deaths in women in the United States, we investigated whether flavopiridol could be an effective agent against a series of isogenic breast- cancer cell lines having different levels of erbB-2 expression and differential invasion and metastatic characteristics. Flavopiridol was found to inhibit the growth of MDA-MB-435 (parental) and 435.eB (stable transfectants) cells that were established by transfecting c-erbB-2 cDNA into MDA-MB-435. Induction of apoptosis was also observed in these cell lines when treated with flavopiridol, as measured by DNA laddering, PARP, and CPP32 cleavages. We also found modest up-regulation of Bax and down-regulation of Bcl-2, but there was a significant down-regulation of c-erbB-2 in flavopiridol-treated cells. Gelatin zymography showed that flavopiridol inhibits the secretion of matrix metalloproteinase (MMP; MMPs 2 and 9) in the breast cancer cells and that the inhibition of c-erbB-2 and MMPs may be responsible for the inhibition of cell invasion observed in flavopiridol-treated cells. Collectively, these molecular effects of flavopiridol, however, were found to be independent of c-erbB-2 overexpression, suggesting that flavopiridol may be effective in all breast cancer. From these results, we conclude that flavopiridol inhibits the growth of MDA-MB-435 breast cancer cells, induces apoptosis, regulates the expression of genes, and inhibits invasion and, thus, may inhibit metastasis of breast cancer cells. These findings suggest that flavopiridol may be an effective chemotherapeutic or preventive agent against breast cancer.
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PMID:Induction of apoptosis and inhibition of c-erbB-2 in breast cancer cells by flavopiridol. 1065 53


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