Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The recent advances in the understanding of the pathogenesis of ovarian cancer have been helpful in addressing issues in diagnosis, prognosis and management. The study of ovarian tumours by novel techniques such as immunohistochemistry, fluorescent in situ hybridisation, comparative genomic hybridisation, polymerase chain reaction and new tumour markers have aided the evaluation and application of new concepts into clinical practice. The correlation of novel surrogate tumour specific features with response to treatment and outcome in patients has defined prognostic factors which may allow the future design of tailored therapy based on a molecular profile of the tumour. These have also been used to design new approaches to therapy such as antibody targeting and gene therapy. The delineation of roles of c-erbB2, c-fms and other novel receptor kinases in the pathogenesis of ovarian cancer has led initially to the development of anti-c-erbB2 monoclonal antibody therapy. The discovery of BRCA1 and BRCA2 genes will have an impact in the diagnosis and the prevention of familial ovarian cancer. The important role played by recessive genes such as p53 in cancer has raised the possibility of restoration of gene function by gene therapy. Although the pathological diagnosis of ovarian cancer is still confirmed principally on morphological features, addition of newer investigations will increasingly be useful in addressing difficult diagnostic problems. The increasingly rapid pace of discovery of genes important in disease, makes it imperative that the evaluation of their contribution in the pathogenesis of ovarian cancer is undertaken swiftly, thus improving the overall management of patients and their outcome.
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PMID:Molecular approaches to diagnosis and management of ovarian cancer. 915 81

Ovarian cancer begins at a molecular level, however to date, our knowledge of genetic changes and mechanisms of ovarian tumorigenesis is limited. The natural history of ovarian cancer may depend on different anatomo-clinical and biological factors. In the life history of ovarian cancers the stage, histology, tumor grade, age of the patient and gene abnormalities, both oncogenes (c-myc, H-ra, new) and oncosuppressor genes (p53, in particular), DNA ploidy and steroid receptor status have important prognostic significance. Residual disease, when less than 1 cm, is another important prognostic factor, being significantly associated to the survival and, progression free, improvement in the survival. In the low stage ovarian cancer (Stage IA, IB, IAII,IBII,IC,IIA,IIB,IIC), adjuvant treatment seems not to influence Disease Free Survival (DFS) or Overall Survival (OS) The exception to this rule is when cisplatin regimen is assessed, as it can highly reduce the relapse rate while the survival is not significantly influenced. Ovarian cancers disseminate, primarily by continuity. Lymphatic dissemination to the pelvic and para-aortic lymph nodes (40% of patients at stage III-IV disease) as well as to the peritoneum is common. At the time of diagnosis, bone or brain metastases are rarely present and their presence is not related to the histology or grading of the tumor.
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PMID:Ovarian cancer: natural history and metastatic pattern. 915 59

Breast cancer is the most common malignancy among women. Genetic predisposition is considered to account for 5-10% of all cases while the majority of these cancers are sporadic and caused by complex interactions of exogenous and endogenous factors. The inherited predisposition can be due to germline mutations in one of several cancer susceptibility genes. For high risk families the two most important genes are BRCA1 on chromosome 17q, which confers a high risk of both, breast and ovarian cancer and BRCA2 on chromosome 13 associated with high penetrance of breast cancer but lower risk of ovarian cancer. A high risk of breast cancer is conferred by mutations in the p53 tumor suppressor gene as part of the rare Li-Fraumeni-syndrome, and possibly also by the estrogen receptor gene. Other cancer genes associated with a less increased risk of breast cancer are the autosomal recessive ataxia telangiectasia (AT) gene and the HRAS1 gene. Germline mutations in BRCA1 and BRCA2 account for the majority of families with multiple cases of breast and/or ovarian cancer and also at least 10% of cases below the age of 40 years. Genetic testing for BRCA1 mutations is not generally recommended except for women with a strong family history. The aim for the management of familial breast cancer should be the establishment of interdisciplinary teams to cover genetic counseling, molecular analysis, onco-surgical therapy, psychosocial support and clinical follow-up.
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PMID:[Molecular genetics of hereditary breast carcinoma]. 917 60

Cancers develop through a succession of stages marked by the accumulation of genetic events within the cell. The rate of occurrence of these events is influenced by the genetic make-up of the individual (e.g., differences in the metabolism of carcinogens, and in the capacity for DNA repair). Knowledge of these events will help define precise targets for early diagnosis. Molecular profiles of cancers will predict prognosis and guide the selection of appropriate therapy. Genetic differences between cancers and normal cells may at last be exploited to make cancer treatment truly selective. An example in clinical trials is the 'smart virus' that replicates in and destroys only cancer cells because of their defective p53 function. An understanding of the genetic background of individuals should allow those at particular risk to be recognised and to develop prevention programmes involving targeted screening or the avoidance of predisposing environmental factors. Here, however, human behaviour and the efficacy of early detection methods are likely to be limiting factors, as is already clear from experience with tobacco smoking and with genes for breast cancer and ovarian cancer.
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PMID:Cancer and genes: how will molecular biology reshape our clinical practice? 917 2

Autoantibodies against complete p53 protein and 18-mer peptides of p53 in ovarian cancer patients and healthy women were examined. Sera from 9% (4/46) of ovarian cancer patients but none (0/51) of healthy women recognized complete p53 protein. The antibodies were mainly of the IgG1 isotype. Two patients had also IgG2 antibodies. Sera from 28% (13/46) of cancer patients and 21% (11/52) of healthy women contained either IgM, or IgM plus IgG2 antibodies against 18-mer p53 peptides. Screening against complete p53 protein instead of peptides seems necessary for identifying patients with tumor-related antibodies. IgG2 antibodies against p53 suggest p53-specific CD4+ T helper 1 cell activity in some of the ovarian cancer patients.
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PMID:Autoantibodies to p53 in ovarian cancer patients and healthy women: a comparison between whole p53 protein and 18-mer peptides for screening purposes. 917 63

The p53 protein is known to play a central role in mediating G1 arrest or apoptosis in response to ionizing radiation in some cell types. It has been proposed that the link between p53 and induction of apoptosis is provided in part by p53-mediated upregulation of BAX. In this study, we used the human SW626 ovarian cancer cell line, which lacks functional p53, to further investigate the relationship between wildtype p53, BAX, and apoptosis. SW626 cells expressing a temperature sensitive (ts) p53 mutant did not undergo G1 arrest or apoptosis and did not exhibit enhanced sensitivity to radiation at the permissive temperature of 32 degrees C. The tsp53 protein was functional in these cells as evidenced by rapid induction of p21 at 32 degrees C, but not at 37 degrees C. Interestingly, restoration of wildtype p53 function at 32 degrees C was not associated with BAX upregulation. In addition, stable overexpression of BAX in SW626 cells was not capable of enhancing apoptotic cell death in response to radiation. Thus, failure of p53 to upregulate BAX is not the sole reason for its inability to promote radiation-induced apoptosis in SW626 cells. Taken together, our data suggest that neither p53 nor BAX upregulation is sufficient for the induction of apoptosis in response to genotoxic damage in some cell types.
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PMID:Radiation-induced apoptosis is not enhanced by expression of either p53 or BAX in SW626 ovarian cancer cells. 919 Aug 90

We have established an ovarian cancer cell line (CABA I) from ascitic fluid obtained from a patient with papillary adenocarcinoma of the ovary prior to drug treatment. The epithelial origin of the cell line was confirmed by morphology and by immunofluorescence analysis using anticytokeratin antibodies. Ultrastructural analysis revealed a very irregular membrane surface and a clear cytoplasm rich in electron-lucent vesicles. CABA I cells grow rapidly in culture (doubling time 18 h) in an anchorage-independent manner. Exogenously added beta-estradiol and epidermal growth factor (EGF) treatments did not influence cell growth rate. FACS analysis to determine the phenotypic profile of tumor-associated antigen, membrane receptor, and adhesion molecule expression indicated that the cell line was positive for different members of the c-erbB family, for alpha 6 and beta 1 integrin receptors, and intensively positive for HLA class I antigens and the folate receptor. Molecular characterization revealed no mutations for c-myc and c-k-ras genes, but did detect an exon 5 mutation in the p53 gene. CABA I cells grew poorly as heterotransplants in nude mice, and tumors showed long latency periods. Because early (15-20) and late (55-60) passage cells maintain the same growth and phenotypic characteristics, the CABA I cell line might provide a good in vitro model system to investigate the cellular and molecular events involved in ovarian carcinogenesis.
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PMID:Ultrastructural and phenotypic characterization of CABA I, a new human ovarian cancer cell line. 922 Apr 98

The frequency of dysfunction of the p53 tumor suppressor gene in cancer has made the concept of gene replacement therapy with wild-type p53 an attractive strategy. Codon 72 of the p53 gene is highly polymorphic with a reported arginine/proline allelotype frequency of 0.65/0.35 for Caucasians and a reversal of this ratio in African-Americans. Ovarian cancer is more common and less aggressive in Caucasians. The arginine and proline alleles have different biochemical properties. Thus, we have hypothesized that these alleles may also have different biologic properties that could make one superior to the other for gene replacement therapy. To test this hypothesis in vivo, we investigated the prevalence of each allelotype in a population of 190 Midwestern American women with ovarian cancer and 52 healthy controls without a family history of cancer. We have found that: (1) the heterozygous arginine/proline allelotype is more common in probands with borderline cancers than in probands with invasive cancers (P = .0001) or healthy controls (P = .005); (2) despite a survival advantage (P = .006), probands homozygous for the arginine allele developed ovarian cancer at an earlier age (P = .01); (3) the frequency of tumor p53 mutations was independent of the germline p53 allelotype, but (4) when a loss of heterozygosity occurred in probands with invasive disease, the proline allele was lost preferentially (P = .002), and (5) any tumor which retained a proline allele was more prone to mutation (P = .04) than a tumor without a proline allele. Our results suggest that variation in the p53 codon 72 allelotype is an example of an intermediate risk polymorphism which interacts with epigenetic factors to play a role in ovarian carcinogenesis and may differentially influence cellular DNA repair and apoptotic pathways. These findings may have important ramifications in the choice of wild-type p53 genotype for gene replacement therapy of ovarian cancer.
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PMID:The influence of the p53 codon 72 polymorphism on ovarian carcinogenesis and prognosis. 925 9

Recently, Frey (Cytometry 17:310-318, 1994) demonstrated that TO-PRO-3 iodide (TP3) can be excited indirectly by a 488 nm laser line through energy transfer by propidium iodide (PI). In the present study, we investigated whether PI-TP3 energy transfer can help to overcome spectral cross talk problems associated with the combined use of fluorescein isothiocyanate (FITC), R-phycoerythrin (PE), and PI. Mixtures of keratin 8/18 FITC-labeled, keratin 8/18-PE-labeled, and unlabeled MCF-7 breast carcinoma cells were prepared and stained for DNA with PI (100 microM). The effect of adding a range of TP3 concentrations (0.001 to 16 microM) to these mixtures was evaluated. The combined use of PI and TP3 was further evaluated using mixtures of unlabeled and p53 FITC-labeled COV362.cl4 ovarian cancer cells and mixtures of unlabeled and p53 FITC-labeled COV362.cl4 cells and peripheral blood lymphocytes (PBL), additionally stained for keratin 8/18 (PE). Finally, a human ovarian ascites tumor specimen was triple-stained for keratin 8/18 (PE), vimentin (FITC) and DNA or keratin 8/18 (PE), PCNA (FITC) and DNA. Addition of TP3 allowed complete correction for spectral cross talk of PE/PI into the green fluorescence detector (FL1). Only minimal (FL1 - %FL2) compensation was required at a TP3 concentration of 2.0 microM in the presence of PI (100 microM). The PI spectral cross talk into the orange fluorescence detector (FL2) was reduced by about 50% using the same photomultiplier (PMT) settings. Although addition of TP3 reduced the signal-to-background ratio by about 30%, the advantage gained through full compensation for spectral cross talk resulted in an improved discrimination of p53-positive and -negative subpopulations in a mixture of human PBL and COV362.cl4 cells. Furthermore, vimentin-negative and PCNA-negative cells were better resolved in a human DNA-aneuploid ovarian ascites tumor after staining the DNA with PI/TP3, rather than with PI alone. We conclude that the addition of TP3 to PI improves the combined measurement by single-laser flow cytometry of DNA-ploidy and antigen expression in heterogenous clinical samples.
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PMID:Improved single laser measurement of two cellular antigens and DNA-ploidy by the combined use of propidium iodide and TO-PRO-3 iodide. 926 54


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