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

Fifty-nine primary breast carcinomas and 11 metastases were examined to identify genetic alterations in the tumour suppressor gene regions 3p, 11p, 13q, 17p, and 17q. Loss of heterozygosity (LOH) was frequently observed on chromosome arms 17p (p144D6 lost in 75%, pYNZ22.1 in 55%, and TP53 in 48% of the primary tumours), 13q (RBI lost in 40% of the primary tumours), and 17q (pRMU3 lost in 35%, pTHH59 in 29%, and NM23HI in 26% of the primary tumours). Loss of all the markers except p144D6 was observed even more frequently in the metastases. Pairwise comparisons for concordance of allele losses on 17p indicated that there might be two genes on 17p implicated in breast cancer development; the TP53 gene and a gene located close to the p144D6 and pYNZ22.1 markers. LOH of the RBI gene was associated with LOH of pYNZ22.1 and p144D6, but not with LOH of TP53. LOH of RBI and TP53 was associated with occurrence of ductal carcinomas, RBI and p144D6 losses with tumour size, and p144D6 losses with positive node status as well. LOH of TP53 and the three 17q markers NM23HI, pTHH59, and pRMU3 was most frequently observed in tumours from postmenopausal women. p144D6 losses occurred most frequently in progesterone receptor-negative tumours, whereas pTHH59 losses occurred most frequently in oestrogen receptor-negative tumours. LOH of the investigated loci was not associated with ERBB2 protooncogene amplification, with positive family history of breast cancer, or with survival.
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PMID:Genetic alterations of the tumour suppressor gene regions 3p, 11p, 13q, 17p, and 17q in human breast carcinomas. 137 10

Apoptotic cells were quantitated by light microscopy in a series of 288 breast carcinomas, and their number (cells/mm2 of neoplastic epithelium, i.e., the apoptotic index, AI) was related to various histopathological features and disease outcome. High AI was associated with tumour necrosis (P = 0.003), lack of tubule formation (P = 0.03), dense stromal lymphocyte infiltration (P = 0.0009), high grade of the tumour (P < 0.0001), DNA aneuploidy (P = 0.049), high S-phase fraction (P = 0.010), high mitotic rate (P < 0.0001), lack of sex steroid receptors (P = 0.004), expression of p53 tumour suppressor gene (P = 0.004), and high values of morphometrically measured nuclear factors (P < 0.05). In survival analysis, an AI greater than 3/mm2 was related to short recurrence-free survival in the entire cohort (P = 0.0079) as well as in the axillary lymph node-negative tumours (P = 0.0253). Survival of the patients with node-negative tumours (P = 0.0356), node-positive tumours (P = 0.0085) and in the entire cohort (P = 0.004) was related to AI. Recurrence-free survival was related to the mitotic index (P = 0.0012), ductal type (P = 0.011), S.D. of the nuclear area (P = 0.075), and axillary lymph node status (P = 0.096). Cox's analysis showed that only the tumour diameter (P < 0.001), axillary lymph node status (P = 0.001), progesterone receptor content (P = 0.004) and ductal type (P = 0.041) had independent prognostic value, whereas AI did not.
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PMID:Apoptosis in breast cancer as related to histopathological characteristics and prognosis. 785 5

Loss of heterozygosity (LOH, allele loss) occurs frequently on the long arm of chromosome 11 in breast cancer. Seventy-one paired tumour/normal DNA samples from breast cancer patients under 50 years old were studied for allele loss at four microsatellite loci on 11q: D11S29 (11q23.3), NCAM (11q22-q23), D11S968 (11qtel), and D11S1313 (11qcen). The maximum frequency of LOH (approximately 35 per cent) was found at the D11S29 and NCAM loci. This result is consistent with previous studies and the frequency of allele loss is moderate to high compared with the usual baseline of 0-20 per cent. In most of the cases studied, LOH on chromosome 11q could be accounted for by one of two mechanisms. Either chromosomal non-disjunction had occurred, or sequences stretching from the telomere at least as far as NCAM had undergone deletion or mitotic recombination. These results suggest that a putative tumour suppressor gene is most likely to exist near 11q22-q23. There was a very low frequency of microsatellite instability in the tumours. An association was found between lack of progesterone receptor (PgR) expression and LOH at NCAM, suggesting that deletion of sequences on 11q may prevent high levels of PgR expression in some cases.
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PMID:The frequency and mechanism of loss of heterozygosity on chromosome 11q in breast cancer. 894 13

Matrix metalloproteinases (MMPs) are a group of enzymes thought to be responsible for both normal connective tissue matrix remodelling and accelerated breakdown associated with tumour development. The current study aimed to investigate the immunohistochemical expression of matrix metalloproteinase 3 (MMP-3, stromelysin-1) in correlation with the expression of Basement Membrane (BM) antigen (type IV collagen, laminin), fibronectin, cathepsin D, p53, c-erbB-2, proliferative activity (Ki-67, PCNA), steroid receptor content as well as to the other conventional clinicopathological parameters in breast cancer. This study was performed on a series of frozen and paraffin sections from 84 breast cancer specimens by immunohistochemistry using the monoclonal antibody MMP-3 (Ab-1). Stromelysin-1 (ST1) was observed in about 10% of epithelial cells in the control groups (cases of fibrocystic and benign proliferative breast disease), while expression (> 10% of expression) was detected in 89.7% of tumours. The expression of ST1 in carcinoma cells was strongly associated with its presence in the stroma (p < 0.001). A significantly positive correlation was found between ST1 expression, and p53 tumour suppressor gene product (p = 0.004), and a relationship with c-erbB-2 protein and progesterone receptor status was also indicated. These findings suggest that ST1 expression in breast cancer tissue is irrespective of the expression of the extracellular matrix component, the proteolytic enzyme cathepsin D and the growth fraction of the tumour, and that it could be a potential new prognostic marker in breast cancer.
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PMID:Matrix metalloproteinase expression in human breast cancer: an immunohistochemical study including correlation with cathepsin D, type IV collagen, laminin, fibronectin, EGFR, c-erbB-2 oncoprotein, p53, steroid receptors status and proliferative indices. 967 87

Prognostic factors, e.g. metastatic disease, lymph node status, tumour size, histologic grade, estrogen and progesterone receptors, and markers of proliferation are used to predict the clinical course of breast cancer at the time of primary treatment. Patients with a poor prognosis are offered adjuvant therapy. For the choice of adjuvant therapy (endocrine or cytotoxic) treatment predictive factors, e.g. estrogen and progesterone receptor; are useful. Putative new prognostic factors (e.g. oncogenes, tumour suppressor genes, and invasive factors) should be evaluated together with the clinical established factors in multivariate analyses.
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PMID:Prognostic factors in breast cancer: a brief review. 970 79

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

Several chromosome regions exhibit loss of heterozygosity (LOH) in human breast carcinoma and are thought to harbour tumour suppressor genes (TSG). At chromosome 13q, two TSGs have been identified, RB1 at 13q14 and BRCA2 at 13q12-q13. In this study, 139 sporadic breast tumours were analysed with 18 polymorphic microsatellite markers for detailed mapping of LOH at chromosome 13q and evaluation of an association with known progression factors. LOH with at least one marker was observed in 71 (51%) of the tumours analysed. The deletion mapping indicated three LOH target regions, 13q12-q13, 13q14 and 13q31-q34. LOH at chromosome 13q12-q13 was associated with low progesterone receptor content, a high S phase fraction and aneuploidy. Multivariate analysis adjusting for lymph node involvement and S phase fraction showed that patients with tumours exhibiting LOH at 13q12-q13 have a 3-4-fold increased risk of recurrence and death compared with other patients. Our results suggest there are at least three separate LOH target regions at chromosome 13q and inactivation of one or more genes at chromosome 13q12-q13 results in poor prognosis for breast cancer patients.
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PMID:Mapping loss of heterozygosity at chromosome 13q: loss at 13q12-q13 is associated with breast tumour progression and poor prognosis. 1007 Mar 14

Reduced expression of BRCA1 has been reported in sporadic breast cancer, although the mechanisms underlying this phenomenon remain unclear. Abnormal methylation leading to silencing of tumour suppressor genes has been implicated in tumorigenesis in a wide range of sporadic cancers. Therefore, we sought to determine the frequency of methylation within the BRCA1 promoter region in a large group of sporadic invasive breast (n =96) and ovarian (n = 43) carcinomas using Southern analyses. Overall, methylation was detected in 11% of breast cancer cases and in 5% of ovarian tumours. Methylation of the BRCA1 promoter region was strongly correlated with lack of estrogen and progesterone receptor expression. It is clear from the frequency of abnormal methylation of the BRCA1 promoter region, that this cannot be the sole mechanism mediating the reduced expression of BRCA1 that has previously been reported to occur in the majority of invasive sporadic breast tumours. Nevertheless this study suggests that abnormal methylation of the BRCA1 promoter may be important in tumorigenesis in a subset of sporadic breast and ovarian cancers.
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PMID:Methylation of the BRCA1 promoter region in sporadic breast and ovarian cancer: correlation with disease characteristics. 1020 17

Similar to findings in colorectal cancers, it has been suggested that disruption of the adenomatous polyposis coli (APC)/beta-catenin pathway may be involved in breast carcinogenesis. However, somatic mutations of APC and beta- catenin are infrequently reported in breast cancers, in contrast to findings in colorectal cancers. To further explore the role of the APC/beta-catenin pathway in breast carcinogenesis, we investigated the status of APC gene promoter methylation in primary breast cancers and in their non-cancerous breast tissue counterparts, as well as mutations of the APC and beta- catenin genes. Hypermethylation of the APC promoter CpG island was detected in 18 of 50 (36%) primary breast cancers and in none of 21 non-cancerous breast tissue samples, although no mutations of the APC and beta- catenin were found. No significant associations between APC promoter hypermethylation and patient age, lymph node metastasis, oestrogen and progesterone receptor status, size, stage or histological type of tumour were observed. These results indicate that APC promoter CpG island hypermethylation is a cancer-specific change and may be a more common mechanism of inactivation of this tumour suppressor gene in primary breast cancers than previously suspected.
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PMID:Adenomatous polyposis coli (APC) gene promoter hypermethylation in primary breast cancers. 1143 4

The tumour suppressor gene TP53 and its downstream effector p21 are thought to play major roles in the development of breast cancer. We investigated three common sequence variants in TP53 and p21 for possible associations with the risk of breast cancer and with various phenotypic features of this disease. A total of 351 cases were available for study. Germline DNA obtained from female subjects of similar age but without cancer was used to estimate the TP53 and p21 genotype frequencies in a control population. A single nucleotide polymorphism in intron 2 of p21 was associated with slightly increased breast cancer risk (RR = 1.4, P = 0.011) and with well/moderately differentiated tumour histology (P = 0.029). The 16 bp insertion polymorphism in intron 3 of TP53 was associated with poor histological grade (OR = 2.3, P = 0.013) independently of other pathological features. The codon 31 polymorphism in p21 was strongly linked to negative progesterone receptor status (OR = 3.4, P = 0.0001), suggesting this variant may have functional significance for the progesterone signalling pathway in breast cancer. These results add to the growing body of evidence that genetic variants can influence not only the risk of breast cancer but also the disease phenotype.
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PMID:Associations between common polymorphisms in TP53 and p21WAF1/Cip1 and phenotypic features of breast cancer. 1187 38


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