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)

Breast cancer is the most common cancer in women worldwide and its incidence is increasing. Oestrogens and mitogenic growth factors may play an important role in the development of breast cancer, whereas inhibitory growth factors may prevent the development of breast cancer. Only about 5 to 10% of cases of breast cancer are due to inheritance of mutations in the BRCA1 or BRCA2 tumour suppressor genes. Mutations in the p53 tumour suppressor gene are commonly found in sporadic breast cancers. Retinoic acid and carotenoids may play a protective role in breast cancer since they inhibit the growth of the oestrogen receptor-positive MCF-7 breast cancer cell line. The presence of oestrogen and progesterone receptors predicts the likelihood of benefit from hormonal therapy. Amplification of the c-erbB2 oncogene in breast cancers is associated with a poor prognosis. It is now apparent that there is a complex, productive cross-talk between oestrogen-directed and growth factor-directed pathways which are believed to markedly reinforce their individual cellular effects on growth and gene responses.
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PMID:Role of steroid hormones and growth factors in breast cancer. 1247 34

The putative role of mannose-6-phosphate/insulin-like growth factor-II receptor (M6P/IGFII-R) as a tumour suppressor and its value as a prognostic marker of breast cancer was studied in 42 benign breast diseases (BBD), 61 in situ carcinomas (CIS) and 133 invasive carcinomas. The receptor was quantified by immunohistochemistry with a computerised image analyser, using specific polyclonal IGY antibodies. The M6P/IGFII-R level varied markedly according to the different patient samples, but median values and distributions were similar in lesions and normal adjacent glands. However, the receptor level was significantly increased in high-grade ductal carcinomas in situ (DCIS) and decreased in invasive carcinomas relative to adjacent normal tissue. The M6P/IGFII-R protein concentration in invasive breast carcinomas was mostly independent of prognostic parameters: tumour size, histological grade, lymph node (N) invasiveness and oestrogen receptor alpha (ERalpha) status. The only positive correlation was with cathepsin D, the progesterone receptor (PgR) and with patients aged >60 years. These results do not support the hypothesis of a frequent and early inactivation of the M6P/IGFII-R gene in breast cancer. Clinical follow-up of patients might reveal a prognostic value for one of the cathepsin receptors.
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PMID:Mannose-6-phosphate/insulin-like growth factor-II receptor expression levels during the progression from normal human mammary tissue to invasive breast carcinomas. 1262 43

To test the hypothesis that altered expression of BRCA1 protein may play an important role in sporadic breast cancer development, 50 randomly selected primary breast cancers (frozen sections, 5 years' median follow-up) were immunolabelled with two monoclonal BRCA1 antibodies (MS110 and MS13). MS110 labelling was exclusively nuclear showing no relation to outcome or tumour pathology. Western blotting demonstrated crossreactivity, suggesting antibody nonspecificity. MS13 labelling was predominantly cytoplasmic. Intense labelling predicted decreased overall survival (P=0.012), disease-free survival (P=0.029), oestrogen receptor negativity (P=0.0004) and c-erbB-2 overexpression (P=0.006). Western blotting detected a 110 kDa molecule consistent with BRCA1 delta11b splice variant. BRCA1 protein is postulated to function as a tumour suppressor. We demonstrate cytoplasmic localisation in sporadic breast cancer suggesting excess delta11b splice variant production, reduced production of full-length BRCA1 and thus postulate reduced tumour suppressor activity. BRCA1 protein appears to have a significant role in both sporadic and hereditary breast cancers.
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PMID:A role for BRCA1 in sporadic breast cancer. 1269 94

Many genetic and environmental factors contribute to development of cancer, but DNA methylation may provide a link between these influences. Genome stability and normal gene expression are largely maintained by a fixed and predetermined pattern of DNA methylation. In cancer, this idealistic scenario is disrupted by an interesting phenomenon: the hypermethylation of regulatory regions called CpG islands in some tumour suppressor genes--eg, BRCA1, hMLH1, p16INK4a, APC, VHL--which causes their inactivation. Development of new techniques that couple bisulphite modification with PCR has enabled these alterations to be studied in all types of biological fluids and archived tissues. Potentially, there are four types of translational studies that can be used to investigate the aberrant pattern of DNA methylation in cancer. First, CpG island hypermethylation can be used as a marker to identify cancer cells from biological samples, eg, serum and urine. This technique is highly sensitive and informative because profiles of tumour-suppressor-gene inactivation are specific to particular cancers. Second, single and combined genes that are inactivated by promoter hypermethylation, such as p16INK4a and DAPK, can be used as prognostic factors. Third, products of genes that are silenced by DNA methylation can be used as biomarkers of response to chemotherapy or hormone therapy--eg, the DNA repair O6-methylguanine-DNA methyltransferase and the oestrogen receptor. Finally, dormant tumour suppressor genes can be reactivated by DNA demethylating drugs, with the aim of reversing the neoplastic phenotype. These are new avenues worth exploring in the fight against cancer.
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PMID:Relevance of DNA methylation in the management of cancer. 1278 7

CTCF is a ubiquitous 11-zinc-finger protein that plays a role in gene silencing or activation, chromatin insulation and genomic imprinting. The CTCF gene has been mapped to the chromosome band 16q22.1 that shows frequent loss of heterozygosity in breast cancer. The E-cadherin gene is the known tumour suppressor gene (TSG) at this region in lobular carcinomas; however, the target gene in the more frequent ductal tumours is still unknown. Since CTCF targets include TSGs and oncogenes and it has the ability to inhibit cell growth and proliferation, it has been suggested that it may be the target gene at the 16q22.1 in ductal carcinomas. In the present study, tissue microarray technology was used to study the expression pattern of CTCF immunohistochemically in 344 cases of invasive breast carcinoma and its expression was correlated with clinicopathological variables and patient outcome. Results showed that breast tissues express CTCF in the parenchymal cells of the normal ducts and lobules but with a variable percentage of positive cells. Staining of CTCF was detected in the nuclei and cytoplasm of the malignant cells, but no significant loss or decrease of expression was noticed in association with any specific tumour type. There was a significant correlation between expression of CTCF and histological grades; lower expression was associated with grade 3 tumours. Cytoplasmic expression was associated with increased tumour size and with the presence of vascular invasion. However, no association was found between CTCF expression and tumour type, lymph node stage, oestrogen receptor expression or patient outcome. In conclusion, the current results show that CTCF, although it may play a role in breast carcinogenesis, is unlikely to be the TSG targeted by the 16q22.1 loss in breast cancer and thus another gene or genes at this region remain to be identified.
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PMID:Expression of the transcription factor CTCF in invasive breast cancer: a candidate gene located at 16q22.1. 1535 17

WEB-2086 -- an antagonist of platelet-activating factor receptor (PAFR) with known anti-inflammatory, antiangiogenic and antileukaemic properties -- also proved to inhibit the proliferation in human solid tumour cell lines of different histology, and with much higher efficacy than in normal fibroblasts. A detailed analysis of WEB-2086 anticancer activity was then performed focusing on breast adenocarcinoma MCF-7 and MDA-MB-231 cells. WEB-2086-treated cells, either expressing (MCF-7) or unexpressing (MDA-MB-231) the oestrogen receptor (ER)alpha, underwent a dose-dependent growth arrest (IC(50)=0.65+/-0.09 and 0.41+/-0.07 mM, respectively) and accumulation in G(0)-G(1) phase. WEB-2086 also induced morphological and functional changes typical of mature mammary phenotype including (i) cell enlargement and massive neutral lipid deposition (best accomplished in MCF-7 cells); (ii) decrease in motility and active cathepsin D levels (mainly observed in highly invasive MDA-MB-231 cells). The expression of ERalpha was neither increased nor reactivated in treated MCF-7 or MDA-MB-231 cells, respectively. WEB-2086-induced differentiation in breast cancer cells involved the upregulation of PTEN, a key tumour suppressor protein opposing tumorigenesis, and was apparently independent of p53, PAFR, peripheral benzodiazepine receptor and ERalpha status. Overall, WEB-2086 can be proposed as an effective antiproliferative and differentiative agent with interesting translational opportunities to treat breast cancers in support to conventional chemotherapy.
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PMID:Growth inhibition and differentiation of human breast cancer cells by the PAFR antagonist WEB-2086. 1672 73

Malignant transformation is a multistep process that may involve dysregulation of oncogenes and tumour suppressor genes, and monoclonal gammopathy of undetermined significance (MGUS) is believed to be a precursor of multiple myeloma. To investigate whether aberrant promoter methylation might be involved in the evolution of MGUS to multiple myeloma, we examined the p16, protein tyrosine phosphatase, non-receptor type 6 (SHP1), death-associated protein (DAP) kinase, E-cadherin and oestrogen receptor genes, most being tumour suppressor genes, by methylation-specific polymerase chain reaction. In 32 cases of multiple myeloma and 19 cases of MGUS, significantly more frequent methylation of p16 (p = 0.001), SHP1 (p< or =0.001) and E-cadherin (p< or =0.001) genes was found in multiple myeloma than in MGUS. Methylation of DAP kinase and oestrogen receptor genes was comparable in multiple myeloma and MGUS. In conclusion, methylation of p16, SHP1 and E-cadherin genes might be involved in the progression of MGUS to multiple myeloma.
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PMID:Aberrant gene methylation implicated in the progression of monoclonal gammopathy of undetermined significance to multiple myeloma. 1721 58

Inter-alpha-trypsin inhibitors (ITIs) are protease inhibitors stabilizing the extracellular matrix. ITIs consist of one light (bikunin) and two heavy chains (ITIHs). We have recently characterized ITIH5, a novel member of the ITIH gene family, and showed that its messenger RNA is lost in a high proportion of breast tumours. In the present study, an ITIH5-specific polyclonal antibody was generated, validated with western blot and used for immunohistochemical analysis on a tissue microarray; ITIH5 was strongly expressed in epithelial cells of normal breast (n=11/15), while it was lost or strongly reduced in 42% (92/217) of invasive breast cancers. ITIH5 expression in invasive carcinomas was associated with positive expression of oestrogen receptor (P=0.008) and histological grade (P=0.024). Correlation of ITIH5 expression with clinical outcome revealed that patients with primary tumours retaining abundant ITIH5 expression had longer recurrence-free survival (RFS; P=0.037) and overall survival (OS; P=0.044), compared to those with reduced expression (mean RFS: 102 vs 78 months; mean OS: 120 vs 105 months). Methylation-specific PCR analysis frequently showed strong methylation of the ITIH5 promoter in primary breast tumours (41%, n=109) and breast cancer cell lines (n=6). Methylation was significantly associated with mRNA loss (P<0.001; n=39), and ITIH5 expression was induced after treatment of tumour cell lines with the demethylating agent 5-aza-2'-deoxycytidine. Moreover, ITIH5 promoter methylation was significantly associated with reduced OS (P=0.008). The cellular function of ITIH5 was evaluated by forced expression of a full-length ITIH5 complementary DNA in the breast cancer cell line MDA-MB-231, which does not endogenously express ITIH5. ITIH5-expressing clones showed a 40% reduced proliferation rate compared to mock-transfected cells. Overall, these data show that promoter methylation-mediated loss of ITIH5 expression is associated with unfavourable outcome in breast cancer patients, and thus ITIH5 could be used as a prognostic marker, although this marker is not multivariate independent due to its close association with ER expression. Our data indicate that ITIH5 is a candidate class II tumour suppressor gene and could be involved in tumour progression, invasion and metastasis, as its absence is associated with increased proliferation rates and a prognostic value indicating poor clinical outcome.
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PMID:The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation. 1765 90

Two novel oestrogen receptor (ER) negative breast cancer cell lines, BCa-11 (familial) and BCa-15 (sporadic) were successfully established from primary tumours. Characterisation of these cell lines showed expression of epithelial specific antigen and cytokeratins confirming their epithelial lineage. Analysis of ultrastructure and anchorage independent growth confirmed the epithelial nature and transformed phenotype of these cells. Both cell lines showed loss of pRb, Dab2 and ERalpha and elevated levels of proliferation marker Ki67. In addition, BCa-11 cells showed loss of HOXA5, tumour suppressor genes p16(INK4A) and RARbeta as well as overexpression of CyclinD1. Elevation of DNMT1 and DNMT3B transcript levels, promoter hypermethylation of RASSF1A, RARbeta2, and HOXA5 further support their neoplastic origin. In conclusion, the two ERalpha negative breast cancer cell lines established herein have certain useful characteristics that may make them valuable for understanding the mechanism of oestrogen receptor negative breast tumours and testing new drugs.
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PMID:Establishment and characterisation of two novel breast cancer cell lines. 1795 94

MicroRNAs are a recently discovered class of small regulatory RNAs that influence the stability and translational efficiency of target mRNAs. They have been implicated in an increasing number of biological processes, including neoplasia. Recent studies have shown an involvement for these regulatory molecules in breast cancer. For example, miRNA profiling studies have identified microRNAs that are deregulated in breast cancer. Furthermore, functional studies have uncovered their roles in breast cancer as both tumour suppressor genes (eg miR-335) and oncogenes (eg miR-21). miRNAs deregulated in breast cancer influence the translational regulation of well-established regulatory molecules, such as oestrogen receptor-alpha, which is regulated by miR-206, and novel cancer-related molecules whose functions are not yet fully understood.. Here we present an overview of our current understanding of miRNA in breast cancer.
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PMID:Small is beautiful: microRNAs and breast cancer-where are we now? 1844 35


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