UMLS:C0178874 - FACTA Search

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Query: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p53 and Rb gene mutations are intermediate biomarkers useful for the prediction of neoplastic progression in bladder cancers. Previously, we have shown that low CYP3A activity, measured by dapsone N-hydroxylation, and high CYP2D6 activity, assessed by debrisoquine 4-hydroxylation, were significant susceptibility risk factors in developing aggressive bladder cancer. However, no information is available about the relationship between drug/xenobiotic metabolizing enzyme activities and p53/Rb mutations that may suggest mechanisms of bladder carcinogenesis. We evaluated in vivo CYP3A activity by the dapsone recovery ratio (DPRR), CYP2D6 activity by the debrisoquine recovery ratio (DBRR), CYP2C19 activity by the mephenytoin R/S ratio (RSR), N-acetyltransferase activity by the monoacetyl dapsone to dapsone ratio and glutathione-S-transferase M1 (GSTM1) genotype by PCR. In immunohistochemical studies of bladder tumor tissue, over expression of p53 protein was detected with antibody pAb1801 and loss of Rb protein expression was evaluated with antibody PMG3-245 in patients with transitional cell carcinoma of the bladder. Low CYP3A activity was significantly associated with over expression of or mutated p53 protein (P < 0.05). High CYP2D6 activity (within the extensive metabolizer group) was significantly associated with loss of expression of or mutated Rb protein (P < 0.05). Positive p53 staining also predicted aggressive bladder cancer histopathology (P < 0.05, odds ratio 2.9), and the lowest tertile of DPRR predicted p53 positivity (P < 0.01, odds ratio 3.9 comparing means of lower tertile versus upper tertile of DPRR). These selective associations are consistent with the hypothesis that an environmental pro-carcinogen fails to be detoxified by CYP3A which may preferentially induce p53 mutations, whereas, an alternative pro-carcinogen that may be activated by CYP2D6, may selectively induce Rb mutations.
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PMID:Association of low CYP3A activity with p53 mutation and CYP2D6 activity with Rb mutation in human bladder cancer. 864 Sep 13

Inactivation of tumor suppressor genes like p53 and p16 play a key role in tumor progression, with a high incidence of mutations existing for both genes in oral squamous cell carcinomas. Previous studies have demonstrated, (i) a correlation between the prevalence of p53 mutations and tobacco use [Brennan et al. (1995) New Engl. J. Med., 332, 712-717; Lazarus et al. (1996) Carcinogenesis, 17, 733-739], and (ii) a link between genotypes in specific xenobiotic metabolizing enzymes and oral cancer susceptibility [Park et al. (1997) Cancer Epid. Biomarkers Prev., 6, 791-797). In this paper, we present results of our examination of a series of 80 oral squamous cell carcinomas for p53 exons 5-9 and p16 exons 1-2 mutations, and the potential association of these mutations with specific genotyping patterns. p53 mutation prevalence in oral tumors was linked with increased patient tobacco use using several stratification criteria. There was a significantly higher prevalence of p53 mutations in OCSCCs from patients who smoked > 30 pack-years as compared to tumors from patients who smoked < or = 30 pack-years (OR = 2.8; CI = 1.1-7.2). No significant association was observed with patient alcohol consumption. There was a significant association between the prevalence of p53 mutations in oral tumors and CYP1A1 genotyping patterns in these oral cancer patients, with the highest p53 mutation prevalence observed in subjects with the CYP1A1 [val]/GSTM1 [+] genotype (OR = 6.0; CI = 1.2-29.7). A significant association was not observed between the prevalence of p16 mutations in oral tumors and tobacco use, or CYP1A1 [val] or GSTM1 (0/0) genotypes. These data suggest that the induction of mutations in specific tumor suppressor genes or oncogenes in oral tumors may be associated with specific carcinogen exposures, and that this association may be linked to specific polymorphic genotypes in xenobiotic-metabolizing enzyme genes.
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PMID:p53, but not p16 mutations in oral squamous cell carcinomas are associated with specific CYP1A1 and GSTM1 polymorphic genotypes and patient tobacco use. 952 87

Dichloroacetic acid (DCA) is a major by-product of water disinfection by chlorination. Several studies have demonstrated that DCA exhibits hepatocarcinogenic effects in rodents when administered in drinking water. This chemical does not appear to be highly mutagenic, and the mechanism(s) involved in DCA induction of cancer are not clear. The present work was aimed at identifying changes in gene expression which may indicate critical alterations/pathways involved in this chemical's carcinogenic activities. We used cDNA microarray methods for analyses of gene expression in livers of mice treated with the tumorigenic dose of 2 g/l DCA in drinking water for 4 weeks. Total RNA samples obtained from livers of the control and DCA-treated mice were evaluated for gene expression patterns with Clontech Atlas Mouse 1.2 cDNA and Atlas mouse stress/toxicology arrays, and the data analyzed with AtlasImage 2.01 and one-way ANOVA in JMP4 software. From replicate experiments, we identified 24 genes with altered expression, of which 15 were confirmed by Northern blot analysis. Of the 15 genes, 14 revealed expression suppressed two- to five-fold; they included the following: MHR 23A, cytochrome P450 (CYP) 2C29, CYP 3A11, serum paraoxonase/arylesterase 1 (PON 1), liver carboxylesterase, alpha-1 antitrypsin, ER p72, glutathione S-transferase (GST) Pi 1, angiogenin, vitronectin precursor, cathepsin D (CTSD), plasminogen precursor (contains angiostatin), prothrombin precursor and integrin alpha 3 precursor (ITGA 3). An additional gene, CYP 2A4/5, had a two-fold elevation in expression. Further, in ancillary Northern analyses of total RNA isolated from DCA-induced hepatocellular carcinomas (from earlier reported studies of mice treated with 3.5 g/l DCA for 93 weeks), many of the same genes (11 of 15) noted above showed a similar alteration in expression. In summary, we have identified specific genes involved in the functional categories of cell growth, tissue remodeling, apoptosis, cancer progression and xenobiotic metabolism that have altered levels of expression following exposures to DCA. These findings serve to highlight new pathways in which to further probe DCA effects that may be critical to its tumorigenic activity.
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PMID:Altered gene expression in mouse livers after dichloroacetic acid exposure. 1264 86

MUC1 is a large transmembrane glycoprotein overexpressed by a majority of carcinomas. High expression of MUC1 is associated with aggressive tumors, and MUC1 antigen is used as a marker to monitor disease progression in breast cancer patients. Several lines of evidence strongly suggest that the overexpression of MUC1 contributes to cancer progression and metastasis. In this report, we demonstrate that the naturally occurring cancer preventative, indole-3-carbinol (I3C), inhibits the expression of MUC1 in breast cancer cells. I3C inhibited both MUC1 mRNA and protein levels in a dose- and time-dependent manner. This inhibition was seen in the estrogen responsive MCF-7 cells as well as unresponsive MDA-MB-468 cells, indicating that the inhibitory pathway is independent of estrogen receptor. Gene expression studies using the human MUC1 gene promoter connected to a luciferase reporter demonstrated that I3C inhibits the transcription of the MUC1 gene. Promoter deletion studies indicate that the region containing up to 600 bp upstream (-600) of the initiation site is sufficient for inhibition by I3C. Furthermore, I3C represses the activation of transcription mediated by the region between -600 and -450 bp. A putative xenobiotic response element was located within this region but the binding of AhR/Arnt heterodimer to this site was undetectable by electrophoretic mobility shift assays. Our results may point to the existence of a novel pathway of transcriptional inhibition by I3C in cancer cells as well as a new mechanism of MUC1 gene inhibition. Our findings might have implications in the use of I3C as a preventative as well as a therapeutic agent for breast cancer.
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PMID:Inhibition of MUC1 expression by indole-3-carbinol. 1502 13

The potential to metabolize endogenous and exogenous substances may influence breast cancer development and tumor growth. Therefore, the authors investigated the protein expression of Glutathione S-transferase (GST) isoforms and cytochrome P450 (CYP) known to be involved in the metabolism of steroid hormones and endogenous as well as exogenous carcinogens in breast cancer tissue to obtain new information on their possible role in tumor progression. Expression of GST pi, mu, alpha and CYP1A1/2, 1A2, 3A4/5, 1B1, 2E1 was assessed by immunohistochemistry for primary breast carcinomas of 393 patients from the German GENICA breast cancer collection. The percentages of positive tumors were 50.1 and 44.5% for GST mu and CYP2E1, and ranged from 13 to 24.7% for CYP1A2, GST pi, CYP1A1/2, CYP3A4/5, CYP1B1. GST alpha was expressed in 1.8% of tumors. The authors observed the following associations between strong protein expression and histopathological characteristics: GST expression was associated with a better tumor differentiation (GST mu, p = 0.018) and with reduced lymph node metastasis (GST pi, p = 0.02). In addition, GST mu expression was associated with a positive estrogen receptor and progesterone receptor status (p < 0.001). CYP3A4/5 expression was associated with a positive nodal status (p = 0.018). Expression of CYP1B1 was associated with poor tumor differentiation (p = 0.049). Our results demonstrate that the majority of breast carcinomas expressed xenobiotic and drug metabolizing enzymes. They particularly suggest that GST mu and pi expression may indicate a better prognosis and that strong CYP3A4/5 and CYP1B1 expression may be key features of nonfavourable prognosis.
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PMID:Expression of xenobiotic and steroid hormone metabolizing enzymes in human breast carcinomas. 1672 11

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the biologic and toxic effects of its xenobiotic ligands. In recent years it has become evident that in the absence of ligand the AHR promotes cell cycle progression and that its activation by high-affinity ligands results in interactions with the retinoblastoma protein (RB) that lead to perturbation of the cell cycle, G0/G1 arrest, diminished capacity for DNA replication and inhibition of cell proliferation. Hence, the AHR has diametrically opposed pro-proliferative and anti-proliferative functions that have yet to be reconciled at the molecular level. Work from our own and from other laboratories suggests that the AHR may function as a tumor suppressor gene that becomes silenced in the process of tumor formation. To develop preliminary support for a more thorough examination of this hypothesis we characterized the expression levels of various tumor suppressor genes, transforming growth factor-beta (Tgfb) genes and the Ahr gene in liver tumor samples from mice with a liver-specific RB ablation and their wild-type littermates. In tumors arising in RB-positive livers, Cdkn2d and Tgfb1 were repressed and Cdkn2c, Tgfb2, Tgfb3 and Pai1 were induced, whereas in RB-negative tumors, only Cdkn2c and Tgfb3 were induced. Ahr was significantly repressed in tumors from both sets of mice, supporting the concept that Ahr silencing may be associated with cancer progression.
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PMID:Repression of Ah receptor and induction of transforming growth factor-beta genes in DEN-induced mouse liver tumors. 1828 51

Low nutritional calcium contributes to disruption of the intestinal epithelial barrier function, to hyperproliferation of colonocytes and increased occurrence of aggressive secondary bile acids in the gut lumen. These mechanisms are also known to be involved in the etiology of colonic inflammation and cancer. We studied in mice and human adenocarcinoma-derived Caco-2 cells the impact of low calcium on markers of inflammation (cyclooxygenase-2; COX-2), of detoxification (pregnane and xenobiotic receptor (PXR)/steroid and xenobiotic receptor (SXR), cytochrome P450 steroid-inducible 3a11 (CYP3A11)), and on expression of the vitamin D system as a protection against tumorigenesis. Caco-2 cells express high COX-2 and low SXR mRNA levels when subconfluent. During differentiation this is reversed, while low calcium enhanced COX-2 protein expression. In vivo low dietary calcium significantly increased the expression of the PXR target gene CYP3A11 in the proximal colon, suggesting compensatory defense mechanisms. In comparison with males, low nutritional calcium elicits a better protective response in females: both the vitamin D synthesizing 25-hydroxyvitamin D(3 )1alpha hydroxylase (CYP27B1) mRNA and the detoxifying CYP3A11 mRNA are augmented more. While it is recognized that colonic vitamin D synthesis may prevent tumor progression, low dietary calcium also elevates the 1,25-(OH)(2)-D(3) catabolic 25-hydroxyvitamin D(3) 24 hydroxylase (CYP24) expression primarily in the proximal colon. Our data suggest the proximal colon as the primary site of response to insufficient calcium intake.
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PMID:Nutritional calcium modulates colonic expression of vitamin D receptor and pregnane X receptor target genes. 1832 73

cDNA micorarray approach was applied to hepatic transcriptional profile analysis in male mouse (Mus musculus, ICR) to assess the potential health effects of drinking water in Nanjing, China. Mice were treated with continuous exposure to drinking water for 90 days. Hepatic gene expression was analyzed with Affymetrix Mouse Genome 430A 2.0 arrays, and pathway analysis was carried out by Molecule Annotation System 2.0 and KEGG pathway database. A total of 836 genes were found to be significantly altered (1.5-fold, P < or = 0.05), including 294 up-regulated genes and 542 down-regulated genes. According to biological pathway analysis, drinking water exposure resulted in aberration of gene expression and biological pathways linked to xenobiotic metabolism, signal transduction, cell cycle and oxidative stress response. Further, deregulation of several genes associated with carcinogenesis or tumor progression including Ccnd1, Egfr, Map2k3, Mcm2, Orc2l and Smad2 was observed. Although transcription changes in identified genes are unlikely to be used as a sole indicator of adverse health effects, the results of this study could enhance our understanding of early toxic effects of drinking water exposure and support future studies on drinking water safety.
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PMID:Gene expression profiles in liver of mouse after chronic exposure to drinking water. 1944 61

CYP1A1 is one of the main cytochrome P450 enzymes, examined extensively for its capacity to activate compounds with carcinogenic properties. Continuous exposure to inhalation chemicals and environmental carcinogens is thought to increase the level of CYP1A1 expression in extrahepatic tissues, through the aryl hydrocarbon receptor (AhR). Although the latter has long been recognized as a ligand-induced transcription factor, which is responsible for the xenobiotic activating pathway of several phase I and phase II metabolizing enzymes, recent evidence suggests that the AhR is involved in various cell signaling pathways critical to cell cycle regulation and normal homeostasis. Disregulation of these pathways is implicated in tumor progression. In addition, it is becoming increasingly evident that CYP1A1 plays an important role in the detoxication of environmental carcinogens, as well as in the metabolic activation of dietary compounds with cancer preventative activity. Ultimately the contribution of CYP1A1 to cancer progression or prevention may depend on the balance of procarcinogen activation/detoxication and dietary natural product extrahepatic metabolism.
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PMID:Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention. 1953 Dec 41

Disulfiram has been used for decades to treat alcoholism. Its therapeutic effect is thought to be mediated by the irreversible inhibition of aldehyde dehydrogenase. Recent reports have indicated new therapeutic uses of disulfiram, in particular in human cancers. Although the biochemical mechanisms that underlie these effects remain largely unknown, certain enzymes involved in cancer processes have been reported to be targeted by disulfiram. Arylamine N-acetyltransferase 1 (NAT1) is a xenobiotic-metabolizing enzyme that biotransforms aromatic amine drugs and carcinogens. In addition to its role in xenobiotic metabolism, several studies have suggested that NAT1 is involved in other physiological and/or pathological processes, such as folate metabolism or cancer progression. In this report, we provide evidence that human NAT1 is a new enzymatic target of disulfiram. We found that disulfiram at clinically relevant concentrations impairs the activity of endogenous NAT1 in human cancer cells. Further mechanistic and kinetic studies indicated that disulfiram reacts irreversibly with the active site cysteine residue of NAT1, leading to its rapid inhibition (IC50 = 3.3 +/- 0.1 microM and k(i) = 6 x 10(4) M(-1) x min(-1)).
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PMID:Mechanisms and kinetics of human arylamine N-acetyltransferase 1 inhibition by disulfiram. 1966 55

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