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

DNA amplification seems to be particularly frequent in human breast tumours and has been associated with cancer evolution and aggressiveness. Recent data indicate that new events should be added to the list, such as the amplifications at chromosome 20q13 or the MDM2 gene. The present work aimed at determining the incidence and clinicopathological signification of these amplifications in a large series of breast and ovarian tumours. We tested 1371 breast and 179 ovarian tumours by Southern blotting and observed amplification of 20q13 in 5.4% breast and 2.8% ovarian carcinomas, whereas MDM2 was found amplified in 5.3% and 3.8% of breast and ovarian tumours respectively. MDM2 RNA expression levels were analysed in a subset of 57 breast tumours and overexpression was observed in 4/57 (7%) of the tumours. Elevated expression levels coincided with amplification of the gene. In breast cancer, 20q13 and MDM2 amplifications seem to define subsets of aggressive tumours. Indeed, 20q13 was correlated to axillary nodal involvement and occurred preferentially in younger patients (< 50 years). Furthermore, 20q13 correlated, as did MDM2 amplification, to aneuploidy. In parallel, we had also tested our tumour DNAs for amplification of CCND1, ERBB-2 and MYC, which made it possible to test for correlations with 20q13 or MDM2 amplifications. Whereas 20q13 showed a very strong correlation to CCND1 amplification, that of MDM2 was prevalent in MYC-amplified tumours. Interestingly, 20q13 and MDM2 amplifications showed some degree of correlation to each other, which may possibly be owing to the fact that both events occurred preferentially in aneuploid tumours. In ovarian cancer, no statistically significant correlation was observed. However, 20q13 amplification occurred preferentially in stage 3 tumours and MDM2 was correlated to ERBB-2 amplification. This may suggest that in ovarian tumours also, 20q13 and MDM2 amplifications occur in late or aggressive cancers.
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PMID:DNA amplifications at 20q13 and MDM2 define distinct subsets of evolved breast and ovarian tumours. 898 Apr 1

The HER-2/neu proto-oncogene encodes a 185 kDa transmembrane receptor tyrosine kinase with significant sequence homology to other members of the class I receptor tyrosine kinase family. The HER-2/neu gene is amplified and/or overexpressed in 25%-30% of human breast and ovarian cancers, and overexpression of the receptor is associated with poor prognosis. Tyrosine phosphorylation and activation of the HER-2 receptor lead to activation of specific signal transduction pathways in breast and ovarian cancer cells, including the ras/MAP kinase cascade, phosphatidylinositol 3-kinase, and phospholipase C-gamma. HER-2/neu signal transduction pathways ultimately converge on the cell nucleus, where the expression of diverse genes is induced after activation of the receptor. A more complete understanding of HER-2/neu signal transduction pathways may allow the development of specific therapeutics for the treatment of those human breast and ovarian cancers containing this alteration.
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PMID:HER-2/neu signal transduction in human breast and ovarian cancer. 900 17

The HER-2/neu proto-oncogene is frequently amplified or overexpressed in human breast and ovarian cancers, and is significantly correlated with shorter survival. We have previously reported that the adenovirus type 5 early region 1A (E1A) gene product can repress HER-2/neu overexpression by repressing HER-2/neu promoter activity, and suppress the tumorigenic potential of HER-2/neu-overexpressing ovarian cancer cells. To examine E1A tumor suppressor function in breast cancer, we transduced E1A in vitro by adenovirus into both HER-2/neu-overexpressing and low expressing human breast cancer cell lines. In HER-2/neu-overexpressing cells, E1A greatly inhibited tumor cell growth in vitro. However, in HER-2/neu low expressing cancer cell lines, E1A had no significant effect on cell growth in culture medium. To test the therapeutic efficacy of E1A, we used both adenovirus-mediated and cationic liposome-mediated E1A gene delivery systems in an orthotopic breast cancer animal model. An advanced breast cancer model was established by inoculation of HER-2/neu-overexpressing human breast cancer cells in mammary fat pad and treated by local injections of either replication-deficient adenovirus expressing E1A, Ad.E1A(+) or a liposome-E1A DNA complex. As controls, mice bearing tumors were also treated with Ad.E1A(-) which is virtually the same adenovirus as Ad.E1A(+) except that E1A is deleted, a liposome-E1A frame-shift mutant DNA complex, or just PBS. In mice bearing a HER-2/neu-overexpressing breast cancer cell line, E1A delivered either by adenovirus or liposome significantly inhibited tumor growth and prolonged mouse survival compared with the controls. In fact, 60-80% of E1A-treated mice lived longer than 2 years versus only 0-20% of control mice (P<0.05). Western blot analysis showed that E1A protein was expressed in tumor tissue and immunohistochemical analysis showed that HER-2/neu p185 protein expression was suppressed. Taken together, our results indicated that both adenovirus and cationic liposome delivery systems were effective in transfering E1A gene for tumor suppression in a HER-2/neu-overexpressing breast cancer model.
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PMID:The tumor suppression activity of E1A in HER-2/neu-overexpressing breast cancer. 905 54

We have previously shown that adenoviral-mediated delivery of an anti-erbB-2 intracellular single-chain antibody (sFv) causes specific cytotoxicy in erbB-2-overexpressing ovarian carcinoma cells. Furthermore, intraperitoneal delivery of the anti-erbB-2 sFv enhances survival and reduces tumor burden in a xenograft model of human ovarian carcinoma in SCID mice. These findings have led to an RAC-approved Phase I clinical trial for patients with ovarian cancer. In this report, we show that expression of the anti-erbB-2 sFv could be readily detected in target tumor cells by in situ hybridization methodology. PCR analysis of DNA extracted from various murine tissues demonstrated that the anti-erbB-2 sFv remained localized to the peritoneum. Delivery of the sFv to the non-erbB-2-overexpressing REN mesothelial and Hep G2 hepatocellular carcinoma cell lines was not deleterious to either one, affirming the tumor specificity of this gene therapy strategy. In addition, histopathological analysis of various tissues showed that adenoviral-mediated delivery of the anti-erbB-2 sFv to immunocompetent mice with either primary exposure or previous vector challenge at different doses produced no abnormal changes when compared to untreated animals. These findings suggest that adenoviral-mediated delivery of the anti-erbB-2 sFv in a human context can be effectively assayed, is potentially free of vector-associated toxicity, and retains biologic utility based on tumor specificity.
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PMID:Transductional efficacy and safety of an intraperitoneally delivered adenovirus encoding an anti-erbB-2 intracellular single-chain antibody for ovarian cancer gene therapy. 906 38

Identifying target antigens for tumor-reactive T cells is important for understanding the mechanisms of tumor escape and developing novel anticancer therapies. To date, mainly CTL responses from tumor infiltrating associated lymphocytes (TIL/TAL) to peptide antigens have been investigated in ovarian cancer. In the present study, the ability of self-peptides derived from HER-2/neu proto-oncogene product (HER-2) to stimulate proliferation of PBMC from healthy donors and ovarian cancer patients has been assessed. Peptide sequences from HER-2 containing anchors for major human MHC-class II molecules have been identified. These peptides induced proliferative and cytokine responses at higher frequency in healthy donors than ovarian cancer patients. Four HER-2 peptides corresponding to positions: 396-406, 474-487, 777-789, and 884-899 were able to stimulate proliferation of a larger number of healthy donors than three other distinct HER-2 peptides 449-464, 975-987 and 1086-1098. The pattern of responses of twenty five ovarian cancer patients was different from that in healthy donors. T cell lines were developed by stimulation with peptides from PBMC of an ovarian cancer patient who showed a stable response to all four HER-2 peptides for over six months. Each T cell line was different in its ability to secrete IFN-gamma and IL-10. These results demonstrate (a) that self-peptides from HER-2 can stimulate expansion of T cells in both healthy donors and ovarian cancer patients, and (b) the ability of different peptides to stimulate secretion of different cytokines from lymphocytes of ovarian cancer patients. These results may be important for understanding the mechanisms of tolerance and autoimmunity in human cancers.
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PMID:Existent proliferative responses of peripheral blood mononuclear cells from healthy donors and ovarian cancer patients to HER-2 peptides. 906 29

Evidence is accumulating for a facilitative role for estrogen in ovarian cancer. Although response to antiestrogen therapy has been poor, there is a distinct subset of patients that respond. Strategies for treatment of ovarian cancer would be improved by identification of patients likely to respond to hormonal therapy. Cell culture models that are responsive or resistant to estrogen and antiestrogen may be of value in finding markers that predict responsiveness to hormonal therapy. Several model cell lines have been generated that express ER and proliferate in response to estrogen in vitro. Further studies are needed to better characterize the response of these ER positive cells lines to estrogen in vivo in mouse xenograft models. Expression of many of the same genes are regulated by estrogen in breast and in ovarian cancer cell lines. One exception may be the HER-2/neu oncogene product, which is down-regulated by estrogen in responsive breast carcinoma cells but not in two ovarian carcinoma cell lines. Initial analyses of several estrogen responsive and one resistant cell model suggests the potential value of progesterone receptor presence and low levels of HER-2/neu expression for predicting responsiveness to hormonal therapy. Additional cell models need to be investigated to determine the frequency with which these markers are associated with antiestrogen resistance.
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PMID:Estrogen action in human ovarian cancer. 913 8

The HER-2/neu (also called c-erbB-2) proto-oncogene is overexpressed in many human cancer cells, including those of breast cancer and ovarian cancer. We have previously shown that adenovirus 5 E1A inhibits HER-2/neu transcription and functions as a tumor suppressor gene in HER-2/neu-overexpressing cancer cells. Liposome-mediated E1A gene transfer suppresses tumor development and prolongs survival of tumor-bearing mice. In support of a phase I clinical trial of an E1A-liposome complex administered to patients with HER-2/neu-overexpressing breast of ovarian cancer, we conducted a series of studies to evaluate the safety of intraperitoneal injection of E1A in normal mice. The cumulative doses used were from five to 40 times the DNA-lipid starting dose proposed for the phase I clinical trial. In this dosing range, the administration of the E1A-liposome complex had no adverse effects on renal, hepatic and hematological parameters studied. No major organ pathologic changes were observed. We concluded that intraperitoneal administration of E1A-liposome complex at the proposed dose would not be expected to produce significant toxicity. The E1A-liposome clinical trial was recently approved by the Recombinant DNA Advisory Committee and Food and Drug Administration for a phase I trial in patients with HER-2/neu-overexpressing breast and ovarian cancer.
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PMID:Safety studies of the intraperitoneal injection of E1A--liposome complex in mice. 913 37

Ovarian cancer is the leading cause of death in gynecological cancers. To date, there are no prognostic factors in ovarian cancer that adequately account for tumor biology and the course of the disease. In recent years, some reports have described the prognostic significance of the amplification and overexpression of the oncogene c-erbB-2 (HER2/neu) in various human cancers, including ovarian cancer. The c-erbB-2 proto-oncogene is located on the long arm of chromosome 17. It encodes a 185 kD transmembrane glycoprotein receptor (p185HER2) that has sequence similarities with the epidermal growth factor receptor (EGF-R). In ovarian cancer, the percentage of c-erbB-2 positive cases varies from 9 to 32%. Correlation with tumor stage and the degree of histological differentiation was not observed. The overexpression of c-erbB-2 is a new and statistically independent prognostic factor. The overexpression of oncogene c-erbB-2 in ovarian cancer can-be detected by immunohistochemistry staining for the protein p185 and characterizes a group with unfavorable tumor biology and a significantly worse prognosis. Elevated serum levels of the c-erbB-2 oncoprotein have been identified in patients with various cancers known to overexpress the c-erbB-2 oncogene. The detection of a p185 oncoprotein fragment in the sera of ovarian cancer patients was recently published by our group. Antiproliferative effects of monoclonal antibodies directed against p185 have been demonstrated in breast cancer patients. This may lead to a new approach in ovarian carcinoma therapy, too, over and above the diagnostic aspects.
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PMID:Overexpression of the oncogene c-erbB-2 (HER2/neu) in ovarian cancer: a new prognostic factor. 913 62

BRCA1 mutations, although implicated in disease predisposition in a major part of the hereditary breast cancer population, do not seem to be crucially involved in tumorigenesis of sporadic breast and ovarian cancers. This suggests that tumours arising in BRCA1 mutation carriers may differ from BRCA1 negative hereditary and sporadic cancer in genetic and biological features, as well as in clinical behaviour. Prior to BRCA1 analysis, 79 breast and 19 ovarian tumours from 57 breast and breast-ovarian cancer families, and 170 tumours from a comparison group of stage II breast cancers were studied with regard to histopathological features; immunohistochemistry [c-erbB-2, p53, oestrogen receptor (ER) and progesterone receptor (PR)], DNA flow cytometry and S-phase fraction. BRCA1 mutations were found in 40 breast and 15 ovarian tumours. The BRCA1 positive breast tumours were significantly more often of ductal type, histological grade III and manifested a heavy lymphocyte infiltration. Additionally, as compared to BRCA1 negative tumours, the BRCA1 positive tumours were significantly more often ER, PgR and c-erbB-2 negative. Furthermore, they were significantly more often DNA non-diploid, as well as being characterised by higher S-phase fraction values. These results suggest that BRCA1-induced breast cancers may manifest distinct tumour biological features of clinical importance.
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PMID:Tumour biological features of BRCA1-induced breast and ovarian cancer. 915 18

We previously demonstrated that delivery of a gene encoding an anti-erbB-2 intracellular single-chain antibody (sFv) resulted in down-regulation of cell surface erbB-2 levels and induction of apoptosis in erbB-2 overexpressing ovarian cancer cells. Based upon these findings, we hypothesized that human breast carcinomas overexpressing erbB-2 would be similarly affected by this genetic intervention. We evaluated the phenotypic effects resulting from intracellular expression of the anti-erbB-2 sFv on the human breast cancer cell lines MDA-MB-361, SK-BR-3, BT-474, MCF-7 and MDA-MB-231. Recombinant adenoviruses encoding either a reporter gene (AdCMVLacZ) or the endoplasmic reticulum (ER) directed anti-erbB-2 sFv (Ad21) were delivered to various breast cancer cell lines. Cell viability was determined by a proliferation assay and fluorescent microscopy allowed visualization of apoptotic cells. An erbB-2 ELISA quantified the endogenous erbB-2 levels of each cell line. The anti-erbB-2 sFv-encoding-adenovirus, Ad21, but not the beta-galactosidase encoding adenovirus, AdCMVLacZ, was cytotoxic to > 95% of the tumor cells in the MDA-MB-361 and SK-BR-3 lines, and > 60% of the tumor cells in the BT-474 line. In marked contrast, the MCF-7 and MDA-MB-231 cell lines showed no change in the rate of cell proliferation following this treatment. The cytotoxic effects generated in the first three lines were a consequence of the induction of apoptosis by the anti-erbB-2 sFv. An ELISA specific for erbB-2 showed that the breast cancer cell lines most susceptible to the anti-erbB-2 sFv, MDA-MB-361, SK-BR-3 and BT-474, overexpressed the erbB-2 protein while the cell lines demonstrating no response to the anti-erbB-2 sFv, MCF-7 and MDA-MB-231, expressed the lowest levels of erbB-2. These results demonstrate that targeted killing of erbB-2 overexpressing cells via intracellular knockout can be accomplished in the context of breast carcinoma. Furthermore, erbB-2 levels in breast tumor cells may be predictive of their sensitivity to sFv-mediated killing. The ability to accomplish selective cytotoxicity of breast cancer cell lines overexpressing the erbB-2 tumor marker should allow for derivation of clinical gene therapy strategies for breast cancer utilizing this approach.
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PMID:An intracellular anti-erbB-2 single-chain antibody is specifically cytotoxic to human breast carcinoma cells overexpressing erbB-2. 917 17


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