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Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abnormalities in the TP53 tumour suppressor gene in 75 atypical ductal hyperplasias and 62 ductalcarcinomas in situ (DCIS) of the breast were studied using immunohistochemistry and mutation analysis. Accumulation of p53 protein was detected in 10 out of 62 (16%) DCIS, whereas no cases of positive staining was observed in the atypical lesions. TP53 mutations were identified in four out of 30 (13%) DCIS by constant denaturant gel electrophoresis (CDGE). Two of these cases were positive and two negative for p53 protein. A total of 12 out of 62 DCIS (19%) carried TP53 mutation and/or p53 protein over-expression. The present results suggest that TP53 alterations may be important in the development of a subset of DCIS.
Breast Cancer Res Treat 1996
PMID:TP53 alterations in atypical ductal hyperplasia and ductal carcinoma in situ of the breast. 894 28

Breast cancer emerges as a multistep process with transformation of normal cells via steps of hyperplasia, premalignant change and in situ carcinoma. Cytogenetic and molecular genetic analyses of breast cancer samples indicate that tumour development involves the accumulation of various genetic alterations, including amplification of oncogenes and mutation or loss of tumour suppressor genes. Microdissection of histological sections is needed to correlate the specific histological change and the genetic alteration. For detection of oncogene amplification quantitative differential polymerase chain reaction (PCR) can be used. For assessment of loss of heterozygosity PCR-based microsatellite polymorphisms detecting differences in short tandem repeat sequences are much more informative than standard two-allele restriction fragment length polymorphism markers. Still, the direct correlation of the genetic alterations to specific histological findings is the key to reveal insight into tumour biology and thereby gain prognostic information for the individual breast cancer patient.
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PMID:Detection of sequential genetic alterations relevant for breast cancer development. 906 Dec 83

The ability of mammalian cells to respond to extrinsic mitogens is downregulated in response to proliferative aging (senescence), and it is now likely that at least a subset of such lifespan checkpoints is triggered by a biological "clock" based on erosion of chromosome telomeres. This review outlines the intrinsic inhibitory signal pathways that link this clock to cell cycle arrest, focussing on the role of tumour suppressor gene products, particularly the p53 and pRb proteins. Emphasis is placed on cell-type specific differences in the timing of lifespan checkpoints, and the "choice" of the underlying inhibitory signal pathway. It is argued that such diversity may explain many differences between cell types in the selection of tumour suppressor gene mutations, providing for example a novel explanation for the difference in molecular pathology and clinical behaviour between two important subsets of human breast cancer.
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PMID:Telomeres, p53 and cellular senescence. 911 31

BRCA1 is a tumour suppressor gene located on chromosome band 17q21. It is estimated that mutations in the BRCA1 gene account for approximately 45% of the breast cancer families and almost all of the breast/ovarian cancer families. We have used single strand conformation polymorphism analysis, direct sequencing, allele specific oligonucleotide hybridisation, and reverse transcription polymerase chain reaction (RT-PCR) to look for mutations in the BRCA1 gene in 49 breast or breast/ovarian cancer families. Five distinct mutations, three novel and two previously observed, were detected in seven families. Each novel mutation was identified in one family: 3896delT in exon 11, a splicing mutation in the intron 9-exon 10 junction, and an inferred regulatory mutation. The 185delAG in exon 2 was found in three families sharing the same haplotype, but this haplotype is different from that shared by the Ashkenazi Jewish families, suggesting that the 185delAG in our families may have arisen independently. Another previously reported mutation, the 3875del4 in exon 11, was identified in one family. Of the 49 families examined, linkage analyses for both the BRCA1 and the BRCA2 regions were performed on 33 families, and mutations in the BRCA1 gene were identified in all but one family that have a lod score above 0.8 for BRCA1. All of the mutations cause either a truncated BRCA1, or loss of a BRCA1 transcript, thus are likely to be functionally disruptive. In addition, we found that alternative splicing is a common phenomenon in the processing of the BRCA1 gene. Seven variant BRCA1 transcripts were identified by RT-PCR; all but one maintained the BRCA1 open reading frame. We believe that alternative splicing may play a significant role in modulating the physiological function of BRCA1.
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PMID:Mutations and alternative splicing of the BRCA1 gene in UK breast/ovarian cancer families. 911 59

A long list of potential prognostic markers has been analysed for breast cancer, some of them will be reviewed in this article. The lymph node status is still the best prognostic marker. The lymph node status combined with information on tumour size, receptor- and proliferation status of the tumour should be analysed as standard for all breast cancer patients. Prognostic information for breast cancer patients has also been described for the membrane protein c-erbB2, the protease cathepsin D, plasminogen activators and inhibitors, certain oncogenes and tumour suppressor genes. Some of these factors also give potential additional information on the response to different oncological therapies, and are better denoted predictive factors. In this overview we shortly describe the above mentioned prognostic factors with major focus on the tumour suppressor gene p53 and its prognostic value and potential predictive value.
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PMID:Overview on human breast cancer with focus on prognostic and predictive factors with special attention on the tumour suppressor gene p53. 914 77

Allelic imbalance or loss of heterozygosity (LOH) studies have been used extensively to identify regions on chromosomes that may contain putative tumour suppressor genes. We looked for evidence of microsatellite instability (MI) and LOH on chromosome 7q, 10q, 11p and 17q using seven polymorphic microsatellite markers. In 42 paired breast cancer-peripheral blood DNA samples we identified 24 tumours (57%) exhibiting genetic alterations. Twenty-one specimens exhibited LOH (50%), while 11 specimens exhibited MI (26%) in at least one microsatellite marker. The most frequent incidence of LOH was found for the marker THRA1 (8/33, 24%) indicating that thra I gene becomes a strong candidate tumour suppressor gene, whereas of MI it was D10S109 (3/26, 12%). These MI and LOH data were analysed using a range of clinicopathological parameters. Tumours displaying MI with no evidence of LOH and tumours exhibiting MI and LOH belonging to stage II or III were found, however none were at stage I. These data suggest that MI may be an early event in mammary tumorigenesis whereas LOH occurs at a late stage. A significant association between the absence of oestrogen receptors (p < 0.01) and the absence of both oestrogen and progesterone receptors (p < 0.001) at 17q21 were observed, indicating a possible relationship between specific genetic changes at this region and hormonal deregulation in the progression of breast cancer.
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PMID:Microsatellite instability and loss of heterozygosity in primary breast tumours. 914 12

Breast cancer is a major cause of morbidity and mortality in women in many parts of the world. Breast carcinomas are heterogenous in their biological and clinical behaviour and a greater understanding of how they develop and progress could lead to more directed forms of screening and therapy. It is important to determine the molecular mechanisms underlying the natural history of breast cancer. Developments in the techniques for molecular analysis have meant that they can now be applied to a large range of clinical material such as cytological preparations and fixed, embedded material, so increasing the potential for relating any molecular alterations to clinical behaviour and response to therapy. In this review we consider recent developments in three areas of importance to breast cancer; genetic analysis-oncogenes, tumour suppressor genes, loss of heterozygosity, microsatellite instability, familial breast cancer; steroid receptors, oestrogen regulated proteins, epidermal growth factor receptor, growth factors particularly transforming growth factor beta; and cell adhesion, invasion and metastasis-E-cadherin, integrins, proteases. These are discussed in relation to potential for screening, prognosis and treatment.
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PMID:Molecular pathology of breast cancer and its application to clinical management. 915 78

Breast cancer emerges by a multistep process which can be broadly equated to transformation of normal cells via the steps of hyperplasia, premalignant change and in situ carcinoma. The elucidation of molecular interdependencies, which lead to development of primary breast cancer, its progression, and its formation of metastases is the main focus for new strategies targetted at prevention and treatment. Cytogenetic and molecular genetic analysis of breast cancer samples demonstrates that tumour development involves the accumulation of various genetic alterations including amplification of oncogenes and mutation or loss of tumour suppressor genes. Amplification of certain oncogenes with concomitant overexpression of the oncoprotein seems to be specific for certain histological types. Loss of normal tumour suppressor protein function can occur through sequential gene mutation events (somatic alteration) or through a single mutational event of a remaining normal copy, when a germline mutation is present. The second event is usually chromosome loss, mitotic recombination, or partial chromosome deletion. Chromosome loci 16q and 17p harbour tumour suppressor genes, which seem to be pathognomonic for the development or progression of a specific histological subtype. There are an overwhelming number of abnormalities that have been identified at the molecular level which fit the model of multistep carcinogenesis of breast cancer. When the functions of all of these genes are known and how they participate in malignant progression, we will have the tools for a more rational approach to diagnosis, prevention and treatment. This review deals only with the factors that are involved in the conversion of a normal breast cell into a malignant cell rather than those required for invasion and metastases. A key critical long-term step in the molecular analysis of breast cancer will be to link the specific molecular damage with the effects of environmental carcinogens.
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PMID:Multistep carcinogenesis of breast cancer and tumour heterogeneity. 923 83

Six hundred and thirty primary breast cancer were screened for abnormalities in exons 5, 6, 7 and 8 of the TP53 tumour suppressor gene. Analysis of the structure of the TP53 gene exons was performed with the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method and with direct sequencing of amplified DNA. In a breast tumour case from a postmenopausal patient, we found a deletion of 36 bp in intron 5 and no immunohistochemical staining for p53. We amplified and sequenced the cDNA region between exons 4 and 7 and showed that the deletion causes the skipping of exon 6. The resulting mRNA sequence had a frameshift that yields an inactive protein with a truncated C terminus. These results show the first example of intronic deletion causing exon skipping at the TP53 gene level.
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PMID:An intronic deletion in TP53 gene causes exon 6 skipping in breast cancer. 933 92

Breast cancer is the commonest malignancy in women and although identification of this multi-system disease has increased, the survival rates have not dramatically altered over the past four decades. Optimium treatment of patients with breast cancer is a subject of great debate and traditionally may be divided into surgery, radiotherapy, chemotherapy and hormone manipulation. Halsted's radical mastectomy, although initially superseded by more mutilating surgery involving removal of tumour, breast, pectoral muscles and axillary contents, has given way to more conservative surgery and breast conservation, so now removal of the tumour with a marginal of healthy tissue is possible. Additional loco-regional radiotherapy has added to the increasing number of treatment options available to both doctor and patient. Systemic adjuvant therapy, primarily hormonal therapy, is used with the aim of decreasing the incidence of recurrence and distant tumour development. Through the process of randomized controlled trials these new therapeutic treatments have shown to be effective in the treatment of locoregional disease. Surgery in patients with advanced systemic disease is limited, however radiotherapy is of considerable importance and can be used to treat or palliate sites of metastases. In recent years trials have assessed chemotherapeutic regimens. However, limited number of patients and adequate randomization have hindered the confident acceptance of these results. Cyclophosphamide, methotrexate and 5 fluorouracil still remain the standard chemotherapeutic regimen, however many new drugs are currently undergoing trials and these or combinations of these may prove to be of future clinical use. Dramatic advances in cell and molecular biology have allowed the development of novel breast cancer therapies. Specific oncogenes and loss of tumour suppressor genes have been associated with decrease patient survival, with the presence of lymph node metastases and with decreased relapse free survival. Growth factor receptor blockers and tyrosine kinase inhibitors may be developed to specifically eradicate breast cancer cells. Immunotherapy and gene therapy may produce effective therapies. Trials utilizing cytokines and trials increasing the immunogenicity of tumours have already reported promising results. Surgery, chemotherapy, radiotherapy and hormone manipulation are the major treatment arms of breast cancer therapy. However, breast cancer still accounts for 20 percent of all female cancer deaths and the overall survival of patients has remained relatively static over the past forty years. From our increasing understanding of the pathological processes involved in the development and spread of breast cancer, new pharmaceutical, immunological and gene therapies may dramatically increase the cure rate of this serious disease.
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PMID:The increasing efficacy of breast cancer treatment. 936 31


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