Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is now possible to detect low copy numbers of messenger ribonucleic acid (mRNA) while retaining good histologic morphology for the determination of specific gene expression in diseased tissues. This technology will allow the pathologist to provide important prognostic information about tumors (expression of oncogenes and growth factors), to identify the subclones within the tumor which may be most likely to metastasize (expression of adhesion molecules and proteases) and to identify etiologic genetic aberrations (viral insertions). A technique for in-situ hybridization to mRNA has been developed for use in formalin fixed paraffin embedded tissues which is suitable for a hospital histology laboratory. Optimal conditions for the procedure were determined by using a biotinylated poly (d)T oligonucleotide probe. Results were dependent on the tissue type, fixation time, condition of the tissue prior to fixation, and degree of digestion before hybridization. The temperature and conditions of hybridization were optimized so that the poly d(T) control probe and the longer test probe could be run simultaneously. Streptavidin and avidin alkaline phosphatase detection systems were tested using levamisole to minimize background staining, and a biotin blocking agent to reduce reaction to renal tubular biotin. Increasing the temperature of stringency washes did not significantly improve the specificity but had a markedly detrimental effect on tissue morphology. The mRNA appears to remain stable within routinely fixed surgical material over long periods of time allowing for large retrospective studies. A review of c-erbB-2 expression in 16 human breast lesions was carried out comparing mRNA in-situ hybridization to immunoperoxidase and cytosolic methods. By direct localization of both message and antigen, it was possible to demonstrate focal positivity that cytosolic methods did not detect. Aberrant translation was noted in one case, and c-erbB-2 expression in non-malignant breast was detected in two cases.
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PMID:mRNA in-situ hybridization using biotinylated oligonucleotide probes: implications for the diagnostic laboratory. 752 37

In search of biomarkers that predict of human prostate cancer progression, we hypothesized that these markers must be expressed in prostatic epithelial cells during multi-step prostate carcinogenesis. Since both genetic and epigenetic factors have been implicated in human prostate cancer development, two osseous-metastatic experimental models were developed in our laboratory, one based on gene transfection and the other on stromal-epithelial interaction studies. In the genetic model, PC-3 cells transfected with point-mutated c-erbB-2/neu oncogene subsequently acquired the potential to metastasize from the prostate to soft tissues and the skeleton. In the epigenetic model, sublines derived from the parental androgen-dependent LNCaP cell line metastasized from the primary tumor to the lymph node and bone. Cells with known lineage relationships were cloned from both the primary and the metastatic tumors and were characterized extensively using cellular, biochemical, immunohistochemical, and molecular techniques. Relevant stage-specific biomarkers associated with prostate cancer progression in these two models were defined and used to evaluate human prostate tissues obtained from the clinic. In this communication, we focused our discussion on the potential importance of c-erbB-2/neu oncogene, vimentin, hepatocyte growth factor/scatter factor and its receptor, c-met oncogene, tumor angiogenesis and neuroendocrine factors as biomarkers for human prostate cancer progression.
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PMID:Biomarkers associated with prostate cancer progression. 752 53

We established a panel of 17 xenografts from primary human breast carcinomas. We examined which characteristics of the original tumours and the xenografts facilitate growth in animals. Tumours expressing medium or strong immunoreactivity for p53 protein had significantly (P < 0.05) higher incidence (92%) of in vivo tumour take than those showing weak or negative immunoreactivity (9.1%). No such association was observed between either c-erbB-2 or epidermal growth factor receptor (EGFR) expression in the original tumours and their in vivo tumour take. Following subcutaneous (s.c.) transplantation of original breast tumours or established xenografts, 7/17 tumours showed metastatic disease spread to distant sites (mainly lungs). This study suggests that selective growth of highly aggressive tumours occurs during in vivo propagation of malignant tumours, and these tumours will be of particular interest in evaluating various chemotherapeutic agents for breast cancer management.
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PMID:Overexpression of mutant p53 and c-erbB-2 proteins and breast tumour take in mice. 757 62

The level of a c-erbB-2 related protein was determined in sera from 168 breast carcinoma patients, 12 females with benign breast disease, and 66 female controls using an ELISA (enzyme linked immunosorbent assay) kit. Elevated c-erbB-2 related protein level was detected in one of 13 preoperative sera (8%), two of 62 postoperative sera from patients without recurrent disease (3%), and 55 of 93 sera collected at recurrent disease (59%). Elevated serum levels were detected significantly more often in patients with distant metastases than in patients with recurrent disease restricted to loco-regional areas (68% versus 19%). Presence of elevated serum level was associated with ERBB2 gene amplification and c-erbB-2 protein overexpression in tumour. None of the patients who had normal ERBB2 gene copy number in tumour had elevated serum levels. Although the usefulness in postoperative prediction of the presence of micrometastases is somewhat questionable, the results suggest c-erbB-2 related protein to represent a novel tumour marker in serum and other body fluids from breast cancer patients at the time of diagnosis and during treatment monitoring.
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PMID:Detection of c-erbB-2 related protein in sera from breast cancer patients. Relationship to ERBB2 gene amplification and c-erbB-2 protein overexpression in tumour. 760 58

In the present study, we aimed to clarify the potential of oncogene amplifications as markers for the prediction of (i) (relapse-free) survival, (ii) response to first-line endocrine therapy and (iii) subsequent chemotherapy in patients with recurrent breast cancer. To attain this goal, amplification of different oncogenes (HER-2/neu, c-MYC and INT-2) was studied in primary tumors of a series of 259 patients with breast cancer (median follow-up of 72 mo). Of these tumors, 49.8% did not contain an amplification of any of the oncogenes studied, whereas in the amplified subgroup, INT-2 was amplified in 13%, HER-2/neu in 24% and c-MYC in 20% of the tumors. In univariate analysis, INT-2 amplification was associated with an increased risk of relapse (p < 0.03), especially in the subgroups of 85 node-negative (p = 0.05) and 156 ER/PgR-positive patients (p = 0.01). Cox multivariate regression analysis showed that c-MYC was the only oncogene whose amplification was significantly related with the rate of relapse. With respect to amplification in patients developing metastatic disease, who received first-line hormonal therapy (n = 114), HER-2/neu amplification was associated with a less favorable response to endocrine therapy (objective response rate only 17% and a progression-free survival (PFS) of only 4% at 12 mo). Interestingly, distinct INT-2 amplification might predict a better response to endocrine therapy (objective response rate of 56%, and a PFS after relapse of 42% at 12 mo).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oncogene amplification and prognosis in breast cancer: relationship with systemic treatment. 760 64

Competitive and differential quantitative PCR methods circumvent the limiting factors of PCR which cause poor reproducibility. We describe the development and performance evaluation of another quantitative PCR method, double-differential PCR (ddPCR). The ddPCR method comprises the co-amplification of the single-copy gene HBB, the erbB-1, erbB-2 and erbB-3 oncogenes and the second single-copy reference gene SOD2 under equal reaction conditions. The ratio of band intensities of the PCR products in silver-stained polyacrylamide gels expresses the average gene copy number (AGCN) per cell of the erbB oncogenes. The coefficient of variability (CV) was less than 25% for an AGCN of 1. The PCR data were in correlation to the results from dot blotting. DNA image analysis did not reveal any correlation between DNA content and gene dosage deviation of the erbB oncogenes. The method was applied to normal breast tissue, benign breast diseases, breast cancer tissue and lymph node metastases. We suggest this method as being reproducible, low cost and rapid, and therefore suitable for clinical studies on erbB oncogene dosage estimation.
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PMID:Double-differential PCR for gene dosage estimation of erbB oncogenes in benign and cancer tissues and comparison to cellular DNA content. 760 69

We have determined the average gene copy numbers (AGCN) of the erbB-1 gene, encoding the epidermal growth factor receptor (EGF-R), the erbB-2 and the erbB-3 genes in breast, ovarian, oral, and lung cancer tissue by using double-differential PCR (ddPCR). The ddPCR method comprises the co-amplification of the single-copy gene HBB, the erbB-1, erbB-2 and erbB-3 oncogenes and the second single-copy reference gene SOD2 under equal reaction conditions. In a retrospective study the AGCN of the erbB genes and the time up to the appearance of metastases were subjected to life-table analysis in 128 women with primary breast cancer. Patients whose breast cancer tissue showed an AGCN for erbB-1 of less than 0.4 and greater then 1.6, as expected from the literature, for erbB-2 of greater than 2.0 and for erbB-3 of less than 1.75 had decreased disease-free survival (DFS). The quotient of erbB-1 and erbB-2 AGCN was the most significant in multivariate Cox analysis followed by nodal status and progesterone receptor status. In extensive studies a similar association between erbB AGCN and metastasis was seen in ovarian cancer and oral cancer, though erbB oncogene aberrations in those entities were not as frequent as in breast cancer. The AGCN of erbB oncogenes may not be of prognostic value in untreated lung cancer patients.
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PMID:Prognostic relevance of aberrations in the erbB oncogenes from breast, ovarian, oral and lung cancers: double-differential polymerase chain reaction (ddPCR) for clinical diagnosis. 760 71

The c-erbB-2 tyrosine kinase is often overexpressed in human breast cancer, but correlations of receptor expression with tumour behaviour have proven elusive in patients without metastases at diagnosis. To address the possibility that receptor function may be more informative than expression, we previously developed function-specific c-erbB-2 antibodies using synthetic tyrosine-phosphorylated peptide immunogens (Epstein et al., Proc. Natl. Acad. Sci. USA 1992; 89: 10435-10439). Here the converse approach has been taken to determine the functional status of c-erbB-2 receptors detected by antibodies to dephosphorylated (dep) autophosphorylation sequences. In contrast to antiphosphopeptide (apt) antibodies, dep antibodies to the Tyr1248 autophosphorylation site exhibited preferential, but not exclusive, binding to tyrosine-dephosphorylated c-erbB-2. Consistent with this, catalytically active and inactive receptors could not be clearly distinguished by in vitro autophosphorylation experiments in which c-erbB-2 was immunoprecipitated using a monoclonal Tyr1248 dep antibody. A dep antiserum recognizing autophosphorylation sites N-terminal to Tyr1248 exclusively recognized tyrosine-dephosphorylated c-erbB-2 following antibody preabsorption with homologous phosphopeptides. Although indirect, these data are consistent with a model of sequential c-erbB-2 autophosphorylation in which Tyr1248 is the final residue modified. Moreover, since many studies of c-erbB-2 expression have used antibodies to dephosphorylated autophosphorylation sites, these results caution against automatically equating such receptor immunoreactivity with in vivo function or clinical significance.
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PMID:Preferential detection of catalytically inactive c-erbB-2 by antibodies to unphosphorylated peptides mimicking receptor tyrosine autophosphorylation sites. 762 46

Overexpression of the c-erbB-2 proto-oncogene has been shown to correlate with relapse and poor prognosis in adenocarcinomas of the breast and stomach. In pancreatic cancer, c-erbB-2 overexpression has been demonstrated using immunohistochemistry, but the relationship between serum c-erbB-2 level and clinical data has not been fully evaluated. In this study, serum c-erbB-2 protein levels were measured in 100 patients with pancreatic adenocarcinomas and in 9 patients with mucin-producing tumors. Immunohistochemical studies for c-erbB-2 protein were performed in 36 patients and 4.0 U/ml in healthy controls (p < 0.001). The positive rate for serum c-erbB-2 was 34% (37/109) in patients with pancreatic cancer and 0% (0/66) in patients with gallstones and in healthy controls (p < 0.001). Immunohistochemical study disclosed that the positive staining rate was 28% (8/29) in common ductal adenocarcinoma specimens, 43% (3/7) in metastasis specimens, and 75% (3/4) in mucin-producing tumor specimens. Clinical evaluation revealed that 59% (22/37) of serum c-erbB-2-positive patients and 33% (24/72) of negative patients had liver or peritoneal metastases (p < 0.01). The mean survival time was 154 days in the c-erbB-2-positive group and 220 days in the negative group (p < 0.05). We suppose that c-erbB-2 is related to metastasis and progression of the disease in patients with advanced pancreatic cancer.
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PMID:Elevated serum c-erbB-2 protein levels in patients with pancreatic cancer: correlation to metastasis and shorter survival. 763 57

The expression of Cath-D c-erbB-2 and EGFR in breast cancer and its correlation of lymphatic metastases were studied in 277 cases by immunohistochemical technique. Positive staining of Cath-D was detected in 107 cases (38.62%), of which, 89 cases (83.17%) had documented metastasis in the lymph nodes. One hundred and seventy cases (61.38%) stained negative for Cath-D, of which 64 cases (37.64%) had detectable lymphatic metastases. There was a significant difference in the rate of the lymphatic metastases between the Cath-D positive and Cath-D negative groups (P < 0.0001). Fifty-six out of 107 Cath-D positive cases (52.34%) were c-erbB-2 positive as well. However, only 27 out of 170 Cath-D negative cases (15.88%) were c-erbB-2 positive. The positive rate of c-erbB-2 in Cath-D positive group was significantly different from that of Cath-D negative group (P < 0.0001). Among those 107 Cath-D positive cases, 49 cases (45.79%) were EGFR positive. Only 24 cases (14.12%) were EGFR positive among the 170 Cath-D negative cases. The positive rate of EGFR between these two groups was also significantly different (P < 0.0001). The results suggest that Cath-D status can be used as an indicator of the aggressiveness of the breast cancer. Breast cancer cases with a positive Cath-D staining are more likely to have lymphatic metastases and a poor prognosis. Therefore, alternative therapeutic strategies and close follow-ups are needed for these patients.
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PMID:[The expression of Cath-D, c-erbB-2 and EGFR in breast cancer and its correlation to lymphatic metastasis]. 765 92


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