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)

An expression vector was constructed from part of pSV2neo with the 3'-ClaI fragment of the epidermal growth factor (EGF) receptor cDNA inserted in an inverted orientation downstream from the human metallothionein (MT) IIa promoter. The human squamous carcinoma cell line NA, which overproduces EGF receptor, was transfected with this vector and selected for resistance to the neomycin derivative G418. One of the stable transfectants had a 90% reduction in cell-surface EGF receptor in response to ZnSO4. The nascent EGF receptor peptide was also decreased with concurrent induction of MT mRNA. These data suggest that the antisense transcript regulated by the MT promoter inhibits the expression of the endogenous EGF receptor genes. Although no transcripts from the antisense gene were detected, the results indicate that transfection with the antisense vector provides a technique by which to modulate the number of EGF receptors on the cell surface of squamous cell carcinomas.
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PMID:Reduction of EGF receptor levels in human tumor cells transfected with an antisense RNA expression vector. 247 67

Human ovarian carcinoma cells (2008 and its cisplatin-resistant sub-line 2008/C13*) were sensitized to cisplatin by treatment with human recombinant gamma interferon (IFN gamma). IFN gamma produced no significant change in the uptake of CDDP. Exposure of 2008 and 2008/C13* cells to IFN gamma resulted in a time-dependent decrease of cellular glutathione and total glutathione-S-transferase activity, principally the pi isoform. By contrast, the treatment of 2008 and 2008/C13* cell lines with IFN gamma induced rather than suppressed metallothionein IIA mRNA levels. IFN gamma changed neither the formation of total platinum-DNA adducts, nor DNA repair. A significant decrease in c-erbB-2 expression was observed both in sensitive and in resistant cell lines after treatment with IFN gamma, and this decrease was dose-dependent. Our results indicate that the mechanism of IFN gamma-induced sensitization in human ovarian-cancer cell lines is multifactorial.
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PMID:Mechanism of interaction between cisplatin and human recombinant interferon gamma in human ovarian-cancer cell lines. 776 37

The protooncogene protein-tyrosine kinase c-fes plays an active role in the induction of terminal myeloid differentiation in myeloid leukemia cells. Although p93c-fes contains two autophosphorylation sites, it is not known what role they play in its catalytic or biological activities. To address this question, the major autophosphorylation site at tyrosine 713 was mutated to phenylalanine (YF713), and the mutated cDNA was expressed in a baculovirus system to assess catalytic activity, as well as in an inducible retrovirus to determine its biological activity. The major phosphopeptide in p93c-fes in vitro contained Y713 and was absent in the YF713 mutant, which exhibited an 85% loss of autophosphorylation activity. The catalytic activity of p93c-fesYF713 with either RCM-lysozyme or poly(Glu,Tyr)4:1 as substrate was reduced by 85 and 78%, respectively, in comparison to p93c-fes. Retroviral infection of K562 cells with the c-fes cDNA under the control of the mouse metallothionein promoter increased superoxide formation, phagocytosis, CD13 and CD33 antigen expression, and doubling time 4-6 days after induction. Cells infected with c-fesYF713 exhibited 40% less superoxide formation but similar levels of phagocytosis, CD13/CD33 antigen, and doubling time in comparison to cells infected with c-fes. The level of phosphotyrosine-containing proteins did not markedly differ between K562 cells expressing either neo, c-fes, or c-fesYF713, with the exception of a reduction in the level of a 210-kDa protein specifically in both c-fes-expressing cell lines. The p210 was tentatively identified as bcr-abl, whose level was also reduced in cells expressing c-fes or c-fesYF713.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of the mutation of tyrosine 713 in p93c-fes on its catalytic activity and ability to promote myeloid differentiation in K562 cells. 833 28

Immunohistochemically detected metallothionein expression [MT(+)] was shown to be related to aggressive behavior of the invasive ductal carcinoma of the breast. In this study, MT expression was examined immunohistochemically in 92 cases of invasive breast carcinoma and compared with immunohistochemically demonstrated estrogen receptor (ER), c-erbB-2, Ki-67 status and clinicopathological characteristics. Of the 92 cases examined, 27.1% (25 cases) were MT(+), and high percentages of the solid tubular subtype of invasive ductal carcinoma (47%), medullary carcinoma (80%), and carcinomas with spindle cell metaplasia (100%) were positive for MT. MT(+) carcinomas showed tendency to have highly atypical nuclei, and nuclear staining for Ki-67 antigen was found in a higher percentage of cases than in MT(-) carcinomas. An inverse relationship between MT(+) and ER immunoreactivity was observed. MT expression was not associated with age distribution, menopausal status, tumor size or lymph node metastasis. The overall survival rate in MT(+) cases was worse than in those negative for MT, but no significant association was found. MT(+) was not associated with poor prognosis in total, estrogen receptor-negative or node-negative tumors. These findings suggest that MT expression in breast cancer cells is related to cell-proliferative activity, and that dedifferentiation of carcinoma cells may play a role in induction of MT expression.
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PMID:Immunohistochemical expression of metallothionein in invasive breast cancer in relation to proliferative activity, histology and prognosis. 860 36

All-trans retinoic acid (ATRA) has been previously shown to inhibit the proliferation of some human ovarian carcinoma cell lines, and this inhibition was accompanied by cellular changes that were indicative of differentiation (Caliaro et al, 1994). In this work, a pretreatment of these adenocarcinoma cells with ATRA, for their respective doubling time, enhanced cisplatin (CDDP) cytotoxicity in the cell ines that were sensitive to its antiproliferative effect, but not in the ATRA-resistant ones. Results were assessed using median effect analysis in two ATRA-sensitive cell lines (OVCCR1 and NIHOVCAR3 cells) and in one ATRA-insensitive cell line (IGROV1 cells). Synergy between these two agents was observed only in cells sensitive to ATRA, regardless of their relative sensitivity to CDDP. Potential mechanisms for this synergy were investigated. ATRA did not increase the cellular platinum content, did not decrease the cellular glutathione and had no influence on the metallothionein IIA mRNA levels in NIHOVCAR3 cells. Moreover, the protein kinase C (PKC) activity was modulated by this differentiating agent in all cell lines tested, indicating that this activity was not directly involved in this potentiation. However, an ATRA inhibition of glutathione-S-transferase activity associated with an increase in the total DNA adducts formation could explain the potentiation of the CDDP cytotoxicity observed in NIHOVCAR3 cells. Finally, the ATRA modulation of the epidermal growth factor (EGF) receptor mRNA level could also be implicated in this synergy.
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PMID:Multifactorial mechanism for the potentiation of cisplatin (CDDP) cytotoxicity by all-trans retinoic acid (ATRA) in human ovarian carcinoma cell lines. 902 Apr 76

Metallothionein (MT) is a low molecular weight, cysteine-rich, zinc-binding protein that may have a function in cellular repair processes, growth and differentiation. Using a monoclonal antibody (E9) to metallothionein, we investigated the immunohistochemical expression of MT in routinely fixed and paraffin-embedded tissue from 98 cases of female breast carcinomas. The MT expression was studied in comparison with the expression of the basement membrane (BM) antigens (type IV collagen, laminin), fibronectin, cathepsin D, adhesion molecule CD44, p53 protein, the pRb, c-erbB-2 oncoprotein, EGFR, stromelysin-1, proliferation indices (Ki-67, PCNA), steroid receptor content as well as with other conventional clinicopathological parameters of breast cancer. Strong MT expression was observed in the majority of tumour cells in 18.4% of tumours, focal MT positivity in 13.3% and almost complete lack of MT expression in 68.4% of cases (mean value 33.36 +/- 26.36). The MT expression in carcinoma cells was strongly associated with the DCIS component of the tumour (p < 0.0001). High values of MT were correlated with low steroid receptor status (p = 0.08 for ER receptor and p = 0.019 for PgR receptor content). MT positive cases were correlated with stromelysin-1 expression (p = 0.059) and cathepsin D (p = 0.058). These findings suggest that MT expression is characteristic of the early phase of breast carcinogenesis, possibly regulated by hormones, and could be a new potential prognostic marker in breast cancer.
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PMID:Immunohistochemical localization of metallothionein in human breast cancer in comparison with cathepsin D, stromelysin-1, CD44, extracellular matrix components, P53, Rb, C-erbB-2, EGFR, steroid receptor content and proliferation. 1047 Jan 61

Advances in molecular and cell biology have led to further understanding of the mechanisms of malignant growth and metastasis in human breast cancer cells. Initiation and progression of breast cancer results from mutations and the abnormal expression of many genes that control cellular proliferation, differentiation, invasion, metastasis and sensitivity to therapy (chemotherapy and radiation therapy). Inhibition of host immunity also plays a role in breast cancer progression. Many genes have been selected as targets for antisense therapy, including HER-2/neu, PKA, TGF-alpha, EGFR, TGF-beta, IGFIR, P12, MDM2, BRCA, Bcl-2, ER, VEGF, MDR, ferritin, transferrin receptor, IRE, C-fos, HSP27, C-myc, C-raf and metallothionein genes. The strategy behind antisense therapy is the development of specific therapeutic agents that aim to correct the mutations and abnormal expression of cellular genes in breast tumour cells by decreasing gene expression, inducing degradation of target mRNA and causing premature termination of transcription. Many in vitro and in vivo studies have investigated the therapeutic efficacy of oligonucleotides and antisense RNAs. These studies have demonstrated specific inhibition of tumour cell growth by antisense therapy and have shown synergistic inhibitory effects between antisense oligonucleotides or antisense RNA and conventional chemotherapeutic drugs used in the treatment of breast cancer. Antisense oligonucleotides have been modified to improve their ability to penetrate cells, bind to gene sequences and downregulate target gene function. Many delivery systems for antisense RNA and antisense oligonucleotides have been developed, including virus vectors (retrovirus, adenovirus and adeno-associate virus) and liposomes, to carry the antisense RNA or oligonucleotides through the cell membrane into the cytoplasm and nucleus of the tumour cells. However, in order to determine their feasibility antisense therapies need to be further investigated to determine their antitumour activity, pharmacokinetics and toxicity in breast cancer patients.
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PMID:Gene targets of antisense therapies in breast cancer. 1222 74

Endometrial adenocarcinoma is the most common malignant neoplasm of the female genital tract and, despite its relative frequency, the molecular events that contribute to the development and progression of the lesion remain poorly understood. The normal human endometrium is characterized by hormone-dependent variations during the menstrual cycle. This tightly controlled system is disturbed in endometrial hyperplasia and carcinomas and a series of changes initiate and promote progression towards the malignant phenotype. These changes can be subdivided into discrete steps, involving activation of oncogenes, inactivation of tumour suppressor genes, deregulation of cell cycle regulators or other proteins involved in tumour invasion and progression. Immunohistochemical expression of different biomarkers such as hormone receptor status (ER, PR), proliferation associated indices (PCNA, MIB1), oncogene (c-erbB-2), tumour suppressor gene products (pRb, p53 protein), cell cycle related proteins (cyclin D1, cyclin E, p21/WAF1), anti-apoptotic protein (bcl-2), adhesion molecule (CD44s), proteolytic enzyme (cathepsin D), heat shock protein (hsp27) and metallothionein (MT) has shown the contribution of these molecules to endometrial carcinogenesis in a hormone-dependent or independent manner as an early or late event. In addition, these biomarkers seem to be correlated with tumour differentiation or myometrial invasion, and therefore could be considered as indicators of the biological behaviour of endometrial carcinoma. Furthermore, the interrelationships of these molecular markers show that these genetic dysregulations could be implicated in the control of cell proliferation and differentiation, and thereby in the multistep process of endometrial carcinogenesis.
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PMID:Immunohistochemical tumour markers in endometrial carcinoma. 1612 80