Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations of the tumour suppressor p53 gene have been reported in a variety of human malignant tumours, and are frequently associated with over-expression of p53 protein. To examine the significance of p53 gene alteration in endometrial carcinomas, we studied the immunohistochemical reactivity with a monoclonal antibody against p53 (PAb 1801) in 30 endometrial carcinomas as well as in 64 normal endometria. The presence or absence of correlation of p53 over-expression with the clinicopathological features and with the immunohistochemical expression of sex steroid receptors (oestrogen receptors; ER, progesterone receptors; PR) was also analysed. Expression of p53 was found in none of 64 normal endometria, but was identified in 5 of the 30 (16.7%) endometrial carcinomas. All 5 of the p53-positive tumours developed in women more than 3 years post-menopause, whereas the carcinomas in 5 pre-menopausal women and 3 women less than 3 years post-menopause were p53-negative. None of the 5 p53-positive carcinomas was associated with adjacent endometrial hyperplasia. Two of the 5 p53-positive tumours showed non-endometrioid histology: serous papillary and clear cell carcinomas. In contrast, 6 carcinomas accompanied by adjacent hyperplasia were p53-negative. In addition, ER and/or PR expression was found in none of the 5 p53-positive tumours, but was present in 21 of the 25 p53-negative tumours (p < 0.01). These clinicopathological features of p53-positive carcinomas and the inverse correlation of p53 immunoreactivity with sex steroid receptor status suggest that p53 over-expression is frequent in a specific category of endometrial carcinoma, presumably oestrogen-unrelated tumours.
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PMID:Immunohistochemical analysis of p53 protein over-expression in endometrial carcinomas: inverse correlation with sex steroid receptor status. 823 23

Chromosome 8 loss of heterozygosity (LOH) in cancer of the urinary bladder is associated with high tumour grade and stage. We have screened 193 cases of transitional cell carcinoma (TCC) of the bladder using 30 microsatellite polymorphisms on chromosome 8. Forty three cases (22%) showed LOH on 8p, the majority of which (72%) had lost the entire short arm. Using 12 tumours with partial deletions of 8p, we have defined a minimum telomeric region of deletion between D8S264 and D8S133 (8p2l.1-pter). We also found LOH in the region 8pl1.2-12, where we have defined at least one centromeric target for deletion within a 4 cM interval. Two tumours were identified with loss of the telomeric region only, whereas all cases with loss in the centromeric region also had telomeric deletion. Chromosome 8p deletions have also been described in prostate, colorectal, hepatocellular, lung and endometrial carcinoma and collecting duct carcinoma of the kidney. It has been postulated that loss or inactivation of at least 2 tumour suppressor genes on 8p may play an important role in progression of both prostate and colorectal carcinomas. The regions of deletion we have identified in bladder tumours are compatible with these, suggesting that at least two genes on 8p may play a role in the development of many common solid tumours. Our findings significantly refine the localisation of the more centromeric of these loci.
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PMID:Deletion mapping implicates two tumor suppressor genes on chromosome 8p in the development of bladder cancer. 864

Apoptosis is a process of single-cell deletion requiring active participation of the cell in its own demise. First described in 1972, it is now known to play a major role in embryogenesis, tissue homeostasis and neoplasia. Apoptosis can be initiated when DNA damage occurs causing the cell to pause in its reproductive cycle. If the DNA damage is beyond repair, the cell proceeds to apoptotic cell death. When the genetic mechanism(s) involved in the pathway of apoptosis is altered, the cell does not die. Further mutations occur by proliferation and such multiple mutational events can lead to a malignant phenotype and cancer growth. The tumour suppressor gene p53 causes a DNA-damaged cell to rest and attempt repair. If damage is irreparable, p53 levels will continue to increase, initiating apoptosis. Mutation of p53, found in approximately 50% of cancers, can stop the apoptotic process. Increased bcl-2 expression, an apoptosis inhibitor, also plays a role in cellular transformation and cancer growth. Its altered expression occurs in the presence of oncogene expression. This paper reviews the role of apoptosis in malignant transformation, cancer growth, and response to therapy for gynaecological cancers. For cervical cancer and its precursors, data on apoptotic index, bcl-2 and Bax expression are presented and discussed in relationship to human papillomavirus expression. In ovarian epithelial malignancies, the role that apoptosis plays in chemotherapeutic responses is reviewed. The data for endometrial cancer are currently limited to apoptotic index.
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PMID:The role of apoptosis in gynaecological malignancies. 918 26

Genetic alterations of tumour suppressor genes, for which loss of heterozygosity (LOH) is one mechanism of gene inactivation, are important steps in the development of endometrial cancer. To investigate the clinical relevance of LOH of BRCA1 (17q21), TP53 (17p13) and TCRD (14q11) in endometrial cancer, polymerase chain reaction (PCR)-based fluorescent DNA technology for the detection of microsatellite polymorphisms was applied. One hundred and thirteen archival endometrial cancer samples with matched normal tissues were examined. Allele loss at three loci were correlated with age, tumour size, lymph node status, metastases, stage, histological types, grade, expression of oestrogen receptor (ER) and progesterone receptor (PgR), family history of cancer, previous history of cancer or precursor lesions, and previous history of hormone replacement therapy (HRT). LOH for BRCA1 was detected in 18.1%, of TP53 in 26.9%, and of TCRD in 26.3% of informative cases. LOH of BRCA1 correlated with medium grade, positive ER status, and family history of cancer; LOH of TP53 correlated with younger age, high grade, positive PgR status, and with tumours from patients without HRT; LOH of TCRD correlated only with family history of cancer. LOH at all three loci correlated only with grade and positive family history. Allele loss of one of the three tumour suppressor loci did not correlate with disease-free survival (DFS), but LOH of BRCA1 correlated significantly with decreased overall survival (OS). The latter, together with the correlation of LOH of BRCA1 locus with steroid hormone receptor expression, might give a hint to the potential involvement of the co-localised 17 beta-hydroxysteroid dehydrogenase (HSD) gene in the development of endometrial cancer.
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PMID:Loss of heterozygosity of BRCA1, TP53 and TCRD markers analysed in sporadic endometrial cancer. 989 67

The roles of the p16 and p15 inhibitor of cyclin-dependent kinase tumour suppressor genes were examined in human uterine cervical and endometrial cancers. p16 mRNA, examined by reverse transcription polymerase chain reaction (RT-PCR), was significantly reduced in five of 19 (26%) cervical and four of 25 (16%) endometrial tumours. Reduced expression of p16 protein, detected by immunohistochemistry, occurred even more frequently, in nine of 33 (27%) cervical and seven of 37 (19%) endometrial tumours. Hypermethylation of a site within the 5'-CpG island of the p16 gene was detected in only one of 32 (3%) cervical tumours and none of 26 endometrial tumours. Homozygous p16 gene deletion, evaluated by differential PCR analysis, was found in four of 40 (10%) cervical tumours and one of 38 (3%) endometrial tumours. Homozygous deletion of p15 was found in three of 40 (8%) cervical tumours and one of 38 (3%) endometrial tumours. PCR-SSCP (single-strand conformation polymorphism) analysis detected point mutations in the p16 gene in six (8%) of 78 uterine tumours (four of 40 (10%) cervical tumours and two of 38 (5%) endometrial tumours). Three were mis-sense mutations, one in codon 74 (CTG-->ATG) and one in codon 129 (ACC-->ATC), both in cervical carcinomas, and the other was in codon 127 (GGG-->GAG) in an endometrial carcinoma. There was one non-sense mutation, in codon 50 (CGA-->TGA), in an endometrial carcinoma. The remaining two were silent somatic cell mutations, both in cervical carcinomas, resulting in no amino acid change. These observations suggest that inactivation of the p16 gene, either by homologous deletion, mutation or loss of expression, occurs in a subset of uterine tumours.
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PMID:Alteration of p16 and p15 genes in human uterine tumours. 1040 54

To obtain functional evidence for DCC as a tumour suppressor associated with endometrial cancer, the human DCC cDNA encoding a complete open reading frame (ORF) was transfected into highly tumorigenic human endometrial carcinoma cells, HHUA and Ishikawa in which DCC expression was completely deleted. Reconstituted expression of DCC in HHUA had little effect on in vitro growth, but suppressed tumour formation in mice completely. The clones from Ishikawa had abundant DCC expression similar to that in normal endometrium. Their growth in vitro was suppressed and showed apoptotic phenotype. Lower levels of DCC expression in the prolonged passaged clones did not induce apoptosis, but still had the potential to suppress tumorigenicity. These observations imply a role of DCC in regulation of normal endometrial cell growth, and categorize DCC as the tumour suppressor gene for endometrial cancer.
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PMID:Suppressed tumorigenicity of human endometrial cancer cells by the restored expression of the DCC gene. 1064 5

Several recent advances have been made in our understanding of the pathogenesis of endometrial tumours, particularly endometrioid endometrial carcinoma (EEC). Mutations in the PTEN gene and microsatellite instability (MSI) are common genetic abnormalities in EECs, and distinguish these lesions from other histological subtypes of endometrial carcinoma. Endometrial precancers are monoclonal lesions that share a common genetic lineage with invasive EEC, including PTEN mutations and MSI. Mutations of the PTEN tumour suppressor gene have been identified in histologically normal-appearing endometrium exposed to oestrogen, 18-55% of endometrial precancers and 26-80% of EECs. PTEN has been shown to play several roles in tumour suppression, including cell cycle arrest and promotion of apoptosis. Loss of PTEN function predisposes endometrial cells to neoplastic transformation, particularly in high-oestrogenic states. MSI is another common alteration seen in EECs and endometrial precancers, and some studies have reported an association between MSI and PTEN mutations. The replication error that results in MSI may facilitate the development of PTEN mutations in some, but not all, cases of EEC. The prognostic significance of PTEN gene mutations and MSI in endometrial carcinoma is controversial. Further study is needed to delineate the different pathogenetic pathways of EEC and their natural history.
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PMID:PTEN mutations and evolving concepts in endometrial neoplasia. 1180 78

The median survival of women with advanced or recurrent endometrial cancer is less than one year. Only half the women with early stage endometrial cancer and poor prognostic factors such as high grade or deep myometrial invasion will survive for 5 years. Over the past decade, incredible strides have been taken in evaluating systemic therapy for this disease. However, survival rates remain poor. A literature search was conducted using CANCERLIT, EMBASE, Medline, Investigational Drug database (Current Drug Ltd.) and R&D Focus (IMSworld Publications). The references of the articles were also explored. Search terms included: endometrial cancer, chemotherapy, endocrine/hormonal therapies, molecular biologics, and specific drug names. Progestin therapy offers a 10-20% response rate and survival of less than 1 year. Progestins are most effective in women with well-differentiated tumours and a long disease-free interval. There is no role for adjuvant progestin therapy in early stage disease. Single-agent chemotherapy with the most activity includes ifosfamide, cisplatin/carboplatin, doxorubicin and paclitaxel. Combination chemotherapy provides a response rate of 40-60%; however, median survival is still less than a year. New areas of research include the identification and evaluation of new active endocrine therapies (i.e. LY353381.HCl and letrozole), chemotherapeutics (i.e. herceptin), evaluating chemotherapeutic agents in combination (i.e. paclitaxel, doxorubicin and platinum), in addition to radiation or instead of radiation. New avenues under development involve the specific molecules and pathways responsible for the initiation and growth of endometrial carcinoma, including: tumour suppressor genes, DNA mismatch repair genes, oncogenes, molecules involved in adhesion and invasion and angiogenesis. Further significant advances in radiotherapy, hormonal therapy and chemotherapy are unlikely. Exciting developments in understanding the molecules involved in tumour development and metastasis will allow the development of specific and selective inhibitors.
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PMID:Current status and future innovations of hormonal agents, chemotherapy and investigational agents in endometrial cancer. 1180 79

Many oncogenes and tumour suppressor genes are connected with the steps of carcinogenesis. Fifteen patients with endometrial cancer were immunohistochemically examined for the presence of abnormal p53 protein. The immunopositivity was comparted in the cancer tissues and analyzed with the conventional clinicopathological prognostic factors as grade, stage, depth of myometrial invasion, lymph-vascular space invasion, metastases in the lymph nodes and metastases in the abdominal cavity. Abnormal expression of p53 was observed in 7 women with endometrial cancer and in 5 patients we observed moderate cytoplasmatic reaction for BCL-2. The correlation between the positive reaction reaction for p53 and BCL-2 means more aggressive tumor, respectively is a bad prognostic factor. The overexpression of p53 is a very important parameter for the progression of the endometrial cancer.
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PMID:[Expression of p53 protein in women with endometrial cancer]. 1180 62

Cyclin E overexpression occurs in a subset of endometrial carcinomas (ECs), but the molecular mechanisms underlying this alteration remain to be established. The present study has analysed amplification of the cyclin E gene (CCNE) and mutation in hCDC4, the gene coding for the F-box protein, which tags phosphorylated cyclin E for proteosomal degradation, to ascertain whether these alterations might be responsible for cyclin E overexpression in ECs. Cyclin E and p53 expression was studied by immunohistochemistry in eight atypical endometrial hyperplasias (AEHs), 51 endometrioid endometrial carcinomas (EECs), and 22 non-endometrioid endometrial carcinomas (NEECs). CCNE amplification was analysed by fluorescence in situ hybridization (FISH). Mutations in exons 2-11 of the hCDC4 gene were screened by PCR-SSCP-sequencing. Finally, the polymorphic marker D4S1610 was used to assess loss of heterozygosity (LOH) in the hCDC4 gene. Cyclin E overexpression was found in 26/81 (32%) cases and was associated with the histological type of the lesion, since it was not found in any AEHs but was present in 27% of EECs and 54.5% of NEECs (p=0.035). Cyclin E overexpression was associated with histological grade (p=0.011) and p53 immunostaining in EECs (p=0.033). CCNE amplification was found in 6 of 37 (16%) ECs examined. There was a significant association between CCNE amplification and the histological type of the lesion, since five (83%) of the six cases with amplification were NEECs (p=0.008). One EEC harboured an hCDC4 mutation: a CGA to CAA (Arg/Gln) change at codon 479. In addition, D4S1610 LOH was found in 7 of 23 (30%) informative cases analysed, but no correlation with cyclin E overexpression was found. However, the tumour with hCDC4 mutation also showed LOH. This is the first study demonstrating that cyclin E overexpression is associated with gene amplification in ECs, these alterations being more frequent in NEECs. Although hCDC4 exhibits a low mutation frequency in ECs overexpressing cyclin E, it seems to function as a tumour suppressor gene that is involved in endometrial carcinogenesis.
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PMID:Cyclin E gene (CCNE) amplification and hCDC4 mutations in endometrial carcinoma. 1464 62


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