Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A principal difference between malignant and normal cells is the aberrant expression of oncogenes. Previously, we have reported on the expression of the insulin-like growth factor 1 receptor (IGF-1-R) in 93% of the human primary breast cancers studied. In the present study, we observed an increased gene copy number of the IGF-1-R in only 19 (2%) of 975 cases studied. The gene copy number of tumors with an amplified IGF-1-R gene varies between 3 and 56 (median, 24 copies). In 11 breast tumor samples with high (greater than or equal to 20 copies) IGF-1-R gene copy numbers, an additional amplification of either the c-myc gene (n = 3) or int-2/bcl-1 genes (n = 5) was observed, whereas no amplification of the HER2/neu gene was detected. The c-fes gene (like the IGF-1-R gene located on chromosome 15q25-qter), was found coamplified with the IGF-1-R in two cases, in one case to the same high extent (38 gene copies, each) and in the other case to only a moderate extent (4 copies of the c-fes gene and 21 copies of the IGF-1-R gene). Tumors with an amplified IGF-1-R gene showed a noticeable increased expression of the IGF-1-R as measured by ligand binding assays on membrane preparations. The median amount of the IGF-1-R protein of the amplified tumors was observed to be 35 times higher when compared to nonamplified tumors (P less than 0.001). Patients with tumors containing a high (greater than or equal to 20 copies) IGF-1-R gene copy number tend to have a shorter median overall survival (42 months; range, 14-120+; n = 8) than patients with tumors having a low amplified (3-10 copies) IGF-1-R gene copy number (median, 77 months; range, 19.5-98+; n = 4).
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PMID:Sporadic amplification of the insulin-like growth factor 1 receptor gene in human breast tumors. 131 Jun 36

Receptor status and gene amplification were studied in advanced human ovarian adenocarcinoma tissues, borderline and benign ovarian tumours and normal ovarian tissues. Sixty-five percent (53/82) of ovarian adenocarcinomas, 57% (8/14) of benign/borderline tumours and only 31% (5/16) of normal ovarian tissues studied showed specific 125I-EGF (epidermal growth factor) binding (median: 17; 10; and 0 fmol EGF-R/mg protein, respectively) and a significant increase in progesterone receptor (PgR) levels was observed in these groups (median: 5; 33; and 152 fmol/mg protein, respectively). No correlations were observed between the levels of EGF-R and the levels of either oestrogen receptors (ER) or PgR. All membrane samples of 25 adenocarcinomas studied by Scatchard analysis were positive for insulin-like growth-factor-I receptors (IGF-I-R) and contained higher IGF-I-R levels than membranes of 10 normal ovarian tissues, of which 9 were positive (median: 64 and 26 fmol IGF-I-R/mg membrane protein, respectively). Also, as measured by autoradiography, 37 adenocarcinoma tissues showed a higher expression of IGF-I-R (1.5+ to 4+) than sections derived from 10 normal ovarian tissues (1+). 125I-IGF-I binding was predominantly associated with epithelial tumour cells, the surrounding connective tissue was negative and in several samples high expression of IGF-I-R was found in areas of tumour necrosis. Southern blot analysis of DNAs isolated from 25 ovarian adenocarcinomas revealed no amplification of the IGF-I-R or the EGF-R gene. The HER2/neu gene was amplified only in 2 out of 3 histologically confirmed endometrioid adenocarcinomas studied but not in 22 other tumours. An amplification of the c-myc gene was observed in 28% (7/25) of the tumours. All c-myc-amplified tumours were PgR-negative. No rearrangement was observed for any of the genes studied. In conclusion, ovarian adenocarcinoma tissues show a decrease in PgR levels and an increased expression of IGF-I-R and EGF-R, in the absence of gene amplification, when compared to benign/borderline ovarian tumours and normal ovarian tissues. In addition, amplification of the c-myc and HER2/neu genes, without rearrangement of these genes, occurs in a minority of these tumours.
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PMID:Receptors for hormones and growth factors and (onco)-gene amplification in human ovarian cancer. 132 50

The expression of oncogene products related to cell growth (c-erbB-2, c-myc, ras p21, EGFR) was investigated in benign (15 cases) and malignant breast lesions (20 cases) by means of immunohistochemistry using the avidin-biotin-peroxidase technique with polyclonal and monoclonal antibodies. The aim of this study was to evaluate the relationship between the staining positivity and various morphological and biological features, such as tumour type, grading, hormone receptor status and cell kinetic parameters. In benign breast lesions, as expected, the kinetic parameters were low, both for Ki-67 and LI. All the specimens showed a diploid condition (the DI being equal to 1) and we found a limited degree of immunoreactivity for all the growth factors and oncogene products. In breast cancer we studied the distribution of immunohistochemical positivity for EGFR, c-erbB-2, c-myc, ras p21 and Ki-67, which was related to age, nodal status, ER and PgR receptor status, LI, DI and histopathological grading. A significant positive correlation was found both between ras p21 expression and nodal status and ER-ICA positivity. We observed a strong correlation between LI and Ki-67 and an inverse relation between Ki-67 and ER expression. These findings suggest the importance of studying the relationship between prognostic factors which may provide preoperative prediction in the biological behaviour of breast cancer, not only on biopsy specimens, but also on fine needle aspirates.
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PMID:Preliminary study on oncogene product immunohistochemistry (c-erbB-2, c-myc, ras p21, EGFR) in breast pathology. 134 7

The frequency of oncogene amplification described in the literature shows a large fluctuation, which could be attributed to the study of relatively small series of tumours, to selection of subgroups of patients, or, especially in retrospective studies, to selection of tumour material from the tumour-bank. To address this question, we have studied amplification of c-myc, HER2/neu and int-2/bcl-1 genes in a series of 1052 collected human breast tumours. The retrospective and prospective subgroups in this collected series of tumours were of equal size. c-myc was amplified in 17.1%, HER2/neu in 18.7% and int-2/bcl-1 in 14.1%, of all breast cancer specimens studied. In the retrospective subgroup the prevalence of amplification was 18.1% for c-myc; 22.6% for HER2/neu and 11.6% for int-2/bcl-1, whereas in the prospective subgroup an incidence of amplification of 16.1%, 15.1% and 16.3% for c-myc, HER2/neu and int-2/bcl-1, respectively was observed. HER2/neu amplification was negatively correlated with oestrogen receptor (ER) and progesterone receptor (PR) status (P less than 0.0001; for both), c-myc amplification was more prevalent in the PR-negative subpopulation (P less than 0.05) and int-2/bcl-1 amplification was positively correlated with ER status (P less than 0.001).
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PMID:Prevalence of amplification of the oncogenes c-myc, HER2/neu, and int-2 in one thousand human breast tumours: correlation with steroid receptors. 135 Apr 57

Amplification of oncogenes in primary tumours may have prognostic and/or therapeutic significance for patients with breast cancer. We have studied HER2/neu and c-myc amplification together with steroid receptors in human primary breast tumours and related the outcome with (relapse-free) survival. A strong inverse correlation was found between HER2/neu amplification and the presence of oestrogen and progesterone receptors. Actuarial 5-years survival showed that breast cancer patients with c-myc amplification in their primary tumours experience a shorter relapse-free survival, especially in node-negative and in receptor-positive tumours, whereas HER2/neu amplification may be of prognostic value for overall survival in receptor-negative tumours. Overall, in our hands, c-myc amplification appeared to be a more potent prognosticator than HER2/neu amplification in human primary breast cancer.
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PMID:Prognostic factors in human primary breast cancer: comparison of c-myc and HER2/neu amplification. 135 12

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

Breast cancer is the most common malignant tumor among women, comprising an estimated 24% of all cancer cases and 18% of all cancer deaths. At least half of the patients with primary breast cancer will ultimately die by metastatic disease. The tumor characteristics, the natural course of the disease and the response to therapy vary strongly. A number of recently detected cell biological parameters such as oncogenes/suppressor genes, growth factors and secretory proteins are more or less important prognostic factors, because they influence the characteristics and behavior of a tumor with respect to metastatic pattern, extent of cellular differentiation, growth rate and response to treatment. However, there is no clear consensus how best to identify patients at high or low risk. In our experience c-myc amplification and pS2 protein are strong prognosticators for relapse rate, while in advanced disease (apart from a negative estrogen/progesterone receptor/pS2 status) amplification of HER2/neu is a good prognosticator for failure to endocrine therapy. In the diagnosis of breast cancer, in vivo imaging of tumors by labeled hormones or other factors also forms a new development which might have implications for treatment too. With respect to treatment both endocrine and chemotherapy can cure a minority of patients with micrometastases, but in patients with advanced disease only a prolongation of (progression-free) survival can be reached. Response rates decrease with increasing tumor load. In the past decade a number of interesting new endocrine agents has been developed such as new (pure) (anti)steroidal agents, vitamins, aromatase inhibitors, analogs of peptide hormones, prolactin inhibitors and growth factor antagonists. However, less is known on the (potential) interaction between hormones, chemotherapeutic agents, retinoids, cytokins, growth factor antagonists and irradiation. Rapid detection of new powerful combination therapies are needed to improve treatment results during the nineties.
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PMID:Clinical breast cancer, new developments in selection and endocrine treatment of patients. 144 97

In 1983, the German Breast Cancer Study Group (GBSG), sponsored by the Federal Ministry of Research and Technology, started a prospective multicenter trial on the treatment of early breast cancer (pT1 pN0 M0). This was preceded by a three-year reviewing period because of some novelties of medical, juristical and ethical problems in the FRG. University and, in the majority, community hospitals participated, combining all together 69 different institutions. From 11/1983 to 12/1989, 1112 patients were recruited. From 1036 patients, 733 underwent breast preservation (71%) and 303 mastectomy (29%). The randomization rate was only 6%. In 268 patients (26%) the tumor size was less than or equal to 10 mm, in 765 patients (74%) 11 to 22 mm. In 129 cases, we subdivided the tumor grading II[3] into IIa and IIb. Moreover, the immunohistochemical detection of the transmembrane proteins EGFR, p-185 and p-148 by oncogene overexpression and c-myc oncogene were undertaken in 425 breast cancers. After tumorectomy (or wide excision) and a lower axillary dissection (at least eight lymph nodes) the breast was irradiated up to 50 Gy in 25 fractions. A boost of 12 Gy was given to the tumor bed. The medial located lymph nodes were also irradiated in case of medially or centrally tumors. Quality control was performed by pathological, radiotherapeutic and methodical reference centers. Significant correlations could be demonstrated between receptor status and tumor grading, patient age and grading, and tumor size and grading. The results emphasize the central role of tumor grading among the prognostic factors. Especially the differentiation of the Bloom and Richardson score II into IIa and IIb seems to play an important role. After a median follow-up of 41 months, the frequency of local recurrences (4.4%), regional recurrences (1%) and distant metastases (4.6%) was exactly the same in both treatment groups. In multivariate analysis, only tumor size and tumor grading had a significant impact on disease-free survival. 23 patients with tumor-involved margins had a higher recurrence rate (DFS 62% versus 85% after five years). Without any impact on DFS were the other conventionally evaluated prognostic factors: age, menopausal status, hormone receptor status, histological tumor type, tumor localisation, degree of differentiation, pleomorphism, mitotic index and degree of dissociation. Among the transmembrane proteins EGFR, p-185, p-148 and c-myc, only the impact of p-185 and EGRF positivity on DSF is significant.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Breast preservation versus mastectomy in early breast cancer--1991 update of the GBSG 1--protocol and prognostic factors. The German Breast Cancer Study Group. 157 68

Ten astrocytomas were tested for gene amplification or rearrangement utilizing distinct probes to nine different oncogenes by Southern hybridization. The probes spanned the four major protein-coding classes of oncogenes; growth factor proteins (csis); growth factor receptor/tyrosine kinase-related proteins [erbB1 (epidermal growth factor receptor, EGF-R), neu (HER2/neu, erbB2), mos, yes]; nuclear binding proteins (c-myc, c-fos); and guanosine 5'-triphosphate binding proteins (N-ras, H-ras). Three astrocytomas, all glioblastomas, showed amplification of EGF-R-related sequences, and two of these amplifications were rearranged. Both rearrangements appeared similar by two different restriction endonucleases. Our findings suggest that it is primarily the EGF-R protooncogene (erbB1) that is amplified or rearranged in astrocytic neoplasms. No other oncogenes were amplified or rearranged, although EGF-R and neu cross-hybridization produced a "pseudo-rearranged" pattern for neu in EGF-R-amplified cases. The similar EGF-R restriction endonuclease abnormalities seen in two patients warrant further study.
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PMID:Oncogene abnormalities in astrocytomas: EGF-R gene alone appears to be more frequently amplified and rearranged compared with other protooncogenes. 167 68

We applied restriction fragment length polymorphism (RFLP) analysis to 24 cases of renal cell carcinomas (RCC), 18 cases of prostate adenocarcinomas (PC), and 11 cases of transitional cell carcinomas (TCC) in the renal pelvis to study the oncogene amplification and inactivation of tumor suppressor genes. All of the cases showed no amplification nor gross rearrangements of the Harvey ras, c-myc, c-fos, c-myb, EGFR and PDGFR. In contrast, RFLP analyses demonstrated allelic losses interpreted as inactivational events of TSGs among the tumor forms studied. RCC had allelic losses on the short arm of chromosome 3 (3p) (68%), the long arm of chromosome 18 (18q) (33%), Y chromosome (29%), and 17p (27%) at high frequencies. PC showed frequent allelic losses on 16q (67%), 8p (50%), 18q (43%), 10p (40%), and 10q (38%). TCC had allelic losses on 17p (73%), 11p (64%), and 9p (40%). It was likely that the cases with the more malignant grade tumor had the more allelic losses.
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PMID:[Oncogene amplification and inactivation of tumor suppressor genes in urological malignant tumors--the application of restriction fragment length polymorphism analysis]. 168 54


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