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)

Several oncogenes and tumour-suppressor genes have been identified that may have an important role in the development of human breast carcinoma. Furthermore, some of these gene alterations may be linked to the development of invasion and subsequent metastasis. Alterations in the expression of ras p21, p53 and c-erbB-2 have all been linked to tumours with rapid cellular proliferation, but the evidence that they are of prognostic importance in patients with breast cancer is conflicting. This study explores the relationship between expression of these oncoproteins and clinical outcome in 92 patients with either locally advanced or metastatic breast cancer treated with primary endocrine therapy. Specimens of the primary carcinoma were available for analysis of hormone receptor, Ki67 labelling index, epidermal growth factor receptor (EGFR), c-erbB-2, p53 and ras p21. Clinical response was measured according to UICC criteria after 6 months of treatment and all patients were followed for time to progression and overall survival. As shown previously, oestrogen receptor (ER) negativity, high Ki67 labelling index and EGFR overexpression were associated with a shorter time to progression and overall survival. However, no statistically significant relationship existed between expression of ras p21, p53 or c-erbB-2 and response to treatment, time to progression or overall survival. We conclude that staining for these three oncoproteins has no role in therapeutic decision-making in patients with advanced breast cancer. The negative finding implies that while abnormal expression of these genes may have an important role in the development of breast cancer, the variations in growth characteristics of advanced breast cancer may be influenced by other factors.
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PMID:Expression of ras p21, p53 and c-erbB-2 in advanced breast cancer and response to first line hormonal therapy. 757 79

Bispecific monoclonal antibodies (BsmAb) can be used to specifically target tumor cells for cytotoxicity mediated by defined effector cells. One such BsmAb, 2B1, targets the extracellular domains of both the c-erbB-2 protein product of the HER-2/neu oncogene and Fc gamma RIII (CD16), the Fc gamma receptor expressed by human natural killer cells, neutrophils, and differentiated mononuclear phagocytes. 2B1 promotes the conjugation of cells expressing these target antigens. It efficiently promotes the specific lysis of tumor cells expressing c-erbB-2 by human NK cells and macrophages over a broad concentration range. 2B1 selectively targets c-erbB-2-positive human tumor xenografts growing in immunodeficient SCID mice. Treatment of such mice with 2B1 plus interleukin 2 (IL-2) inhibits the growth of early, established human tumor xenografts overexpressing c-erbB-2. A phase I clinical trial of 2B1 has been initiated to determine the toxicity profile and maximum tolerated dose (MTD) of this BsmAb and to examine the biodistribution of the antibody and the biologic effects of treatment. Preliminary results of this trial indicate that the dose-limiting toxicity for patients with extensive prior bone marrow-toxic therapy is thrombocytopenia for as yet undetermined reasons. Toxicities of fevers, rigors, and associated constitutional symptoms are explained, in part, by treatment-induced systemic expression of cytokines, such as tumor necrosis factor-alpha. Circulating, functional BsmAb is easily detectible in treatment patients' sera and exhibits complex elimination patterns. HAMA and anti-idiotypic treatment-induced antibodies are induced by 2B1 treatment. Some preliminary indications of clinical activity have been observed. BsmAb therapy targeting tumor antigens and Fc gamma RIII has potent immunologic effects. Future studies will include the development of more relevant animal models for BsmAb therapy targeting human Fc gamma RIII. The ongoing phase I trial will be completed to identify the MTD for patients without extensive prior bone marrow-toxic chemotherapy and radiation. A phase II clinical trial of 2B1 therapy in women with metastatic breast cancer is planned, as is a phase I trial incorporating treatment with both 2B1 and IL-2.
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PMID:Clinical development of 2B1, a bispecific murine monoclonal antibody targeting c-erbB-2 and Fc gamma RIII. 858 84

We have analyzed serum levels of soluble HER-2/neu in 42 primary breast cancer patients prior to any therapy and studied the relationship between the overexpression and amplification of HER-2/neu in the primary tumor after surgical excision and data obtained by pathohistological staging. In addition, we have investigated the sera of 62 patients with stage IV breast cancer. Using an enzyme-linked immunosorbent assay, we observed elevated serum HER-2/neu levels in 6/42 (14.2%) preoperative patients. In 42.8% of the patients with HER-2/neu tumor expression/amplification serum levels were increased. In contrast, only 8.5% of the patients without HER-2/neu expression/amplification in the primary tumor presented with elevated serum levels. There was a significant correlation between serum concentrations of soluble HER-2/neu and tumor size (p < 0.0001) or axillary lymph node involvement (p < 0.0001). In patients with stage IV disease, 27 of 62 (43.5%) had elevated soluble HER-2/neu serum levels. A highly significant correlation between soluble HER-2/ neu and CA 15-3 (p < 0.002) was observed. The correlation of serum concentrations of HER-2/neu with estrogen and progesterone receptor status of the primary tumor was not significant in both groups. In conclusion, the measurement of serum HER-2/neu levels at diagnosis defines a small subgroup of breast cancer patients with a relatively advanced stage of disease. Its strong correlation with tumor load in patients with stage II disease and the high prevalence in patients with stage IV disease could make it a promising tool for the assessment of disease activity and biologic behavior in breast cancer.
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PMID:Tissue expression and serum levels of HER-2/neu in patients with breast cancer. 939 44

The relationship between c-erbB-2 serum positivity and prognosis was evaluated in 80 patients with metastatic breast cancer. Using 120 fmol/ml as a cutoff level, elevated concentrations were found in 31 patients (38.8%) at the time of detection of metastases. Menopausal status, steroid receptor status, site of recurrence, initial tumor size, initial degree of nodal involvement as well as relapse-free interval were unrelated to c-erbB-2 serum positivity. In addition, no association could be found between adjuvant chemotherapy and positive c-erbB-2 concentrations. Patients with elevated c-erbB-2 levels showed a lower response rate (including complete remission, partial remission, no change) to first-line therapy than those with normal levels (29 vs. 59%, p < 0.01). The median survival time after relapse was 12 months (CI: 3-22 months) for the c-erbB-2-negative patients and only 6 months (CI: 3-8 months) for the c-erbB-2-positive group (p < 0.01). In the multivariate analysis, while c-erbB-2 levels at the time of primary surgery had no significant impact on survival in metastatic breast cancer, serum c-erbB-2 turned out to be the strongest factor for predicting survival after relapse.
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PMID:The prognostic significance of c-erbB-2 serum protein in metastatic breast cancer. 942 73

HER-2/neu is a growth factor receptor, the expression of which has been associated with a more aggressive breast tumor biology and resistance to some types of chemotherapy. Preliminary laboratory and clinical data have led to claims that HER-2/neu expression is also associated with resistance to tamoxifen. Therefore, to test the hypothesis that HER-2/neu expression is associated with a poorer response to tamoxifen, a shorter time to treatment failure (TTF), and worse survival in estrogen receptor (ER)-positive metastatic breast cancer, we examined 205 paraffin-embedded blocks of tumors from patients enrolled on Southwest Oncology Group 8228 for HER-2/neu expression. Tumors were ER positive (ER level > 3 fmol/mg cytosolic protein in either primary tumors or metastases), and patients had not received any prior therapy for metastatic disease. All patients were treated with daily tamoxifen. The study began in 1982, and median follow-up of patients who are still alive is now 9 years. Membrane staining for HER-2/neu was evaluated by immunohistochemistry using antibody TAB 250 and was scored according to the proportion of cells staining positive; tumors were deemed positive if > 1% of the cells stained for HER-2/neu. HER-2/neu positivity was associated with lower ER values (P = 0.04) and low bcl-2 (P = 0.01). HER-2/neu positivity was not significantly associated with response rate (negative versus positive, 57 versus 54%; P = 0.67), TTF (median, 8 versus 6 months; P = 0.15), or survival (median, 31 versus 29 months; P = 0.36). There was also no significant evidence of a progressive relationship between an increasing proportion of cells expressing HER-2/neu and a shorter TTF or survival. HER-2/neu expression in ER-positive metastatic breast cancer is not significantly associated with a poorer response to tamoxifen or a more aggressive clinical course. Earlier suggestions to the contrary may have been due to failure to rigorously exclude ER-negative tumors, which are much less likely to respond to tamoxifen and more likely to have high HER-2/neu levels.
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PMID:HER-2 expression and response to tamoxifen in estrogen receptor-positive breast cancer: a Southwest Oncology Group Study. 951 46

We determined cytosol c-erbB-2 protein levels using a sandwich enzyme immunoassay in benign breast disease and primary and recurrent breast cancer and analyzed the relationship between c-erbB-2 protein levels and clinicopathological factors. Overexpression of c-erbB-2 protein, the cut-off value being set at 18 ng/mg protein, was observed in 26 of the 139 cases of stages I-IIIB breast cancer (18.7%), four of the 12 cases of stage IV breast cancer (33.3%) and seven of the 13 recurrent breast cancer cases (53.8%). The levels of c-erbB-2 protein were significantly different between the stages. Overexpression of c-erbB-2 protein in stages I-IIIB breast cancer was associated with histological grade and serum CEA level, but not with other clinicopathological factors. In addition, there was an inverse correlation in the group of stages I-III plus IV breast cancer between c-erbB-2 protein expression and estrogen receptor status. Overexpression of c-erbB-2 protein can be easily determined in the cytosol fraction together with hormonal receptor by this method. The prognostic importance will be evaluated in ongoing adjuvant trials for operable breast cancer patients.
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PMID:Determination of cytosol c-erbB-2 protein in breast cancer by sandwich enzyme immunoassay. 954 22

IIB-BR-G is an undifferentiated, highly heterogeneous, hormone receptor negative human breast cancer cell line previously established in our laboratory from a patient's primary tumor. An in vitro growing cell line (IIB-BR-G) and a xenotransplanted tumor growing in nude mice (IIB-BR-G(NUDE)) were derived. To further characterize these systems, immunocytochemical analysis was performed for differentiation antigens (PEM 200 kDa, CEA, NCA 90 kDa), blood-group related antigens (Le(x), sTn), oncogenes and tumor suppressor gene products (Her-2/neu protein, p53), metastasis-related cathepsin D and CD63/5.01 Ag, and the chemokine monocyte chemotactic protein 1 (MCP-1). Expression of markers was heterogeneous in these different systems. Previously reported karyotypic analysis has shown extensive chromosomal alterations including double min. Searching for oncogene amplification, we detected augmented copy number of c-myc and c-fos, the last one with two rearranged fragments. No amplification was found for c-erbB-2 in the cell line or in IIB-BR-G(NUDE), although this oncogene was amplified in the patient's primary tumor DNA. The differences observed between the patient's tumor, the cell line and the IIB-BR-G(NUDE) tumors are probably due to clonal expansion of cell variants not present in the original tumor. Electron microscopy of IIB-BR-G growing cells revealed epithelial characteristics with abundant dense granules, presumably secretory, distributed all over the cytoplasm and great nuclear pleomorphism. In vitro, IIB-BR-G cells showed a significant number of invading cells by Matrigel assay. After nearly 40 sequential subcutaneous passages of the original xenograft through nude mice, 80% of recipients developed spontaneous metastases, primarily to the lung and lymph nodes. Since this experimental model allowed to analyze changes produced in cancer cells from the primary tumor during adaptation to in vitro and in vivo growth, our results provide novel insights on the behaviour of hormone independent metastatic breast cancer.
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PMID:The human breast cancer cell line IIB-BR-G has amplified c-myc and c-fos oncogenes in vitro and is spontaneously metastatic in vivo. 962 Apr 46

We established an RT-PCR method to measure the amount of a 2.3-kb alternatively spliced mRNA of the human c-erbB-2/HER-2 proto-oncogene relative to the 4.6-kb full-length transcript. For the first time, we demonstrated production of c-erbB-2 extracellular domains via alternative splicing in breast cancer tissues, lymph node and bone marrow micrometastases. In 15 c-erbB-2-positive primary breast tumor samples, we found two significantly distinct subgroups: 6/15 had a low level of the extracellular fragment, and 9/15 showed an average 4.4-fold higher amount of the alternatively spliced mRNA. Additionally, six lymph nodes and six bone marrow aspirates from metastatic breast cancer patients were analyzed: 5/6 lymph nodes and 6/6 bone marrow aspirates were found to produce elevated relative amounts of the truncated fragment. The results demonstrate that our method is suitable for sensitive detection of c-erbB-2-positive micrometastasis and strongly suggest that the alternatively spliced c-erbB-2 variant is involved in the development of micrometastasis in breast cancer.
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PMID:Differential expression of alternatively spliced c-erbB-2 mRNA in primary tumors, lymph node metastases, and bone marrow micrometastases from breast cancer patients. 964 24

The study was designed to identify factors that could predict response to chemotherapy in breast cancer. A total of 173 patients with measurable or evaluable metastatic breast cancer were enrolled in a randomized trial between November 1987 and January 1991 to receive a monthly dose of 5-fluorouracil (500 mg m(-2)), epirubicin (60 mg m(-2)) and cyclophosphamide (500 mg m(-2)) either administered in four weekly doses or in an every-4-week dose as first-line cytotoxic treatment. In 103 evaluable patients we performed a multivariate analysis of the tumour biological factors, i.e. histological grade, oestrogen receptor (ER), progesterone receptor (PR), S-phase fraction (SPF), ploidy, p53, c-erbB-2, Bcl-2 and Bax expression, which showed significance in the univariate analysis according to treatment response, time to progression (TTP) or overall survival (OS). In the univariate analysis only SPF, grade and the proapoptotic protein Bax correlated with the response to cytotoxic treatment. In the multivariate analysis SPF had the strongest correlation, followed by grade and Bax. In the univariate analysis grade, PR, Bax and Bcl-2 correlated significantly with TTP, whereas in the multivariate analysis only PR showed a statistically significant correlation. In the univariate analysis PR and Bax correlated with OS and both retained its significance in the multivariate analysis. The factors that correlated significantly with the response to cytotoxic treatment in the univariate analysis, i.e. grade, SPF and Bax, seemed to predict independently the response to treatment in the multivariate analysis also. TTP and OS could be predicted partly by the same factors, although the association was quite weak. More studies and new tumour biological factors are needed to identify the group of breast cancer patients who get the most benefit from chemotherapy.
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PMID:A multivariate analysis of tumour biological factors predicting response to cytotoxic treatment in advanced breast cancer. 974 6

The HER-2/neu oncogene encodes a transmembrane tyrosine kinase receptor with extensive homology to the epidermal growth factor receptor. HER-2/neu has been widely studied in breast cancer. In this review, the association of HER-2/neu gene and protein abnormalities studied by Southern and slot blotting, immunohistochemistry, enzyme immunoassays, and fluorescence in situ hybridization with prognosis in breast cancer is studied in depth by review of a series of 47 published studies encompassing more than 15,000 patients. The relative advantages of gene amplification assays and frozen/fresh tissue immunohistochemistry over paraffin section immunohistochemistry are discussed. The significance of HER-2/neu overexpression in ductal carcinoma in situ and the HER-2/neu status in uncommon female breast conditions and male breast cancer are also considered. The potential value of HER-2/neu status for the prediction of response to therapy in breast cancer is presented in the light of a series of recently published studies showing a range of impact on the outcome of patients treated with hormonal, cytotoxic, and radiation therapies. The evidence that HER-2/neu gene and protein abnormalities in breast cancer predict resistance to tamoxifen therapy and relative sensitivity to chemotherapy regimens including adriamycin is presented. The review will also evaluate the status of serum-based testing for circulating the HER-2/neu receptor protein and its ability to predict disease outcome and therapy response. In the final section, the review will briefly present preliminary data concerning the use of antibody-based therapies directed against the HER-2/neu protein and their potential to become a new modality for breast cancer treatment. The recently presented phase III clinical trial evidence that systemic administration of anti-HER2 antibodies (Herceptin), alone and in combination with cytotoxic chemotherapy in patients with HER-2/neu overexpressing primary tumors, can increase the time to recurrence and overall response rates in metastatic breast cancer is reviewed.
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PMID:The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. 983 67


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