Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SNPs in CYP1A1, CYP2A1, CYP2B6, CYP2C, CYP2D6, CYP3A, GSTM1, GSTT1, GSTP1, SULT1A1, SULT1A2, UGT, and MTHFR are associated with breast cancer susceptibility; however, lack of such associations are also reported in some populations. The contradictory findings are explained on the basis of ethnic variation among populations and due to lack of proper sample size, detailed genotype-phenotype combinations and validation of gene expression studies at protein level. In this review, SNPs in these genes that have tremendous potential in identification of susceptible individuals, development of preventive strategies, treatment outcomes and their limitations are discussed.
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PMID:Do single nucleotide polymorphisms in xenobiotic metabolizing genes determine breast cancer susceptibility and treatment outcomes? 1879 70

Aberrant hypermethylation of promoter regions in specific genes is a key event in the formation and progression of cancer. In at least some situations, these aberrant alterations occur early in the formation of malignancy and appear to be tumour specific. Multiple reports have suggested that measurement of the methylation status of the promoter regions of specific genes can aid early detection of cancer, determine prognosis and predict therapy responses. Promising DNA methylation biomarkers include the use of methylated GSTP1 for aiding the early diagnosis of prostate cancer, methylated PITX2 for predicting outcome in lymph node-negative breast cancer patients and methylated MGMT in predicting benefit from alkylating agents in patients with glioblastomas. However, prior to clinical utilisation, these findings require validation in prospective clinical studies. Furthermore, assays for measuring gene methylation need to be standardised, simplified and evaluated in external quality assurance programmes. It is concluded that methylated genes have the potential to provide a new generation of cancer biomarkers.
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PMID:Methylated genes as new cancer biomarkers. 1913 39

Bilaterality of breast cancer is an indicator of constitutional cancer susceptibility; however, the molecular causes underlying this predisposition in the majority of cases is not known. We hypothesize that epigenetic misregulation of cancer-related genes could partially account for this predisposition. We have performed methylation microarray analysis of peripheral blood DNA from 14 women with bilateral breast cancer compared with 14 unaffected matched controls throughout 17 candidate breast cancer susceptibility genes including BRCA1, BRCA2, CHEK2, ATM, ESR1, SFN, CDKN2A, TP53, GSTP1, CDH1, CDH13, HIC1, PGR, SFRP1, MLH1, RARB and HSD17B4. We show that the majority of methylation variability is associated with intragenic repetitive elements. Detailed validation of the tiled region around ATM was performed by bisulphite modification and pyrosequencing of the same samples and in a second set of peripheral blood DNA from 190 bilateral breast cancer patients compared with 190 controls. We show significant hypermethylation of one intragenic repetitive element in breast cancer cases compared with controls (P = 0.0017), with the highest quartile of methylation associated with a 3-fold increased risk of breast cancer (OR 3.20, 95% CI 1.78-5.86, P = 0.000083). Increased methylation of this locus is associated with lower steady-state ATM mRNA level and correlates with age of cancer patients but not controls, suggesting a combined age-phenotype-related association. This research demonstrates the potential for gene-body epigenetic misregulation of ATM and other cancer-related genes in peripheral blood DNA that may be useful as a novel marker to estimate breast cancer risk. ACCESSION NUMBERS: The microarray data and associated .BED and .WIG files can be accessed through Gene Expression Omnibus accession number: GSE14603.
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PMID:Gene-body hypermethylation of ATM in peripheral blood DNA of bilateral breast cancer patients. 1915 73

In this study, we sought to assess the aberrant methylation of multiple tumor-suppressor genes in a single reaction by using methylation-specific multiplex ligation-dependent probe amplification. Breast tumors and corresponding normal tissues of 77 patients were analyzed. In this study, 17 of 24 genes displayed promoter methylation in one or more of the tumor samples. The most frequently methylated genes were RASSF1 and GSTP1, followed by DAPK1 and CDKN2B. Our data indicate that the methylation of specific genes is a frequent event in breast cancer and show that MS-MLPA is a powerful tool to analyze epigenetic alterations for diagnostic, as well as therapeutic, purposes.
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PMID:Methylation profiles in breast cancer. 1919 28

Oxidative metabolites of estrogens have been implicated in the development of breast cancer, yet relatively little is known about the metabolism of estrogens in the normal breast. We developed an experimental in vitro model of mammary estrogen metabolism in which we combined purified, recombinant phase I enzymes CYP1A1 and CYP1B1 with the phase II enzymes COMT and GSTP1 to determine how 17beta-estradiol (E(2)) is metabolized. We employed both gas and liquid chromatography with mass spectrometry to measure the parent hormone E(2) as well as eight metabolites, that is, the catechol estrogens, methoxyestrogens, and estrogen-GSH conjugates. We used these experimental data to develop an in silico model, which allowed the kinetic simulation of converting E(2) into eight metabolites. The simulations showed excellent agreement with experimental results and provided a quantitative assessment of the metabolic interactions. Using rate constants of genetic variants of CYP1A1, CYP1B1, and COMT, the model further allowed examination of the kinetic impact of enzyme polymorphisms on the entire metabolic pathway, including the identification of those haplotypes producing the largest amounts of catechols and quinones. Application of the model to a breast cancer case-control population defined the estrogen quinone E(2)-3,4-Q as a potential risk factor and identified a subset of women with an increased risk of breast cancer based on their enzyme haplotypes and consequent E(2)-3,4-Q production. Our in silico model integrates diverse types of data and offers the exciting opportunity for researchers to combine metabolic and genetic data in assessing estrogenic exposure in relation to breast cancer risk.
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PMID:Estrogen metabolism and breast cancer: a risk model. 1925 Jan 93

Recent findings indicate a greater risk of postmenopausal breast cancer with estrogen-progestagen therapy than estrogen monotherapy, and more so for current than past use. Few studies have examined individual genetic susceptibility to the effects of menopausal hormone therapy. We used two population-based case-control studies with 3,155 postmenopausal breast cancer patients and 5,496 controls to evaluate modification of breast cancer risk associated with duration of hormone use by genes involved in hormone metabolism and detoxification. Twenty-eight polymorphisms in eight genes of phase I (CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP3A4, CYP3A5, CYP3A7) and nine genes of phase II enzymes (COMT, GSTM1, GSTM3, GSTP1, GSTT1, SULT1A1, UGT1A1, UGT1A6, UGT2B7) were genotyped. The risk associated with duration of use of combined estrogen-progestagen therapy was significantly modified by genetic polymorphisms located in CYP1B1, GSTP1, and GSTT1. In homozygote carriers of the CYP1B1_142_G and the CYP1B1_355 _T variant alleles, adjusted odds ratios (OR) per year of use were 1.06 (95% confidence interval (CI) = 1.02-1.09) and 1.06 (95% CI = 1.03-1.09), respectively, compared with 1.02 (95% CI = 1.01-1.03) in non-carriers of either polymorphism (p(interaction) = 0.01). Carriers of the functional GSTT1 allele and the GSTP1_341_T allele were at significantly higher risks associated with hormone use compared with non-carriers (p(interaction) = 0.0001 and 0.02). CYP1A1_2452_C>A significantly reduced the risk associated with duration of use of estrogen monotherapy (p(interaction) = 0.01). The finding regarding GSTT1 was still statistically significant after corrections for multiple comparisons. Postmenopausal breast cancer risk associated with hormone therapy may be modified by genetically determined variations in phase I and II enzymes involved in steroid hormone metabolism.
Breast Cancer Res Treat 2010 Jan
PMID:Genetic polymorphisms in phase I and phase II enzymes and breast cancer risk associated with menopausal hormone therapy in postmenopausal women. 1942 94

Breast cancer is the most common cancer among women worldwide and second in Thailand. Glutathione S-transferase (GST) enzymes involved in the detoxification of reactive metabolites of carcinogens may be important in modulating susceptibility to cancers. This study aimed to determine the influence of genetic polymorphisms of glutathione S-transferase T1, M1, P1 and A1 on breast cancer in Thai patients. Links with clinico-pathological characteristics were also analyzed. The results showed no association between GSTs polymorphism and overall susceptibility to breast cancer in Thai patients (P < 0.05). However, the data pointed to a relation of the GSTP1(Ile105Val) polymorphism with progesterone receptor status (P = 0.04) and age at diagnosis (P = 0.03) of breast cancer cases. In summary, this is the first study to report associations between glutathione S-transferase T1, M1, P1 and A1 gene polymorphisms and breast cancer in Thai patients. While GST genotypes may not be associated with susceptibility, a GSTP1 polymorphism (Ile105Val) may be related to progression of breast cancer.
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PMID:Glutathione s-transferase polymorphisms in breast cancers of Thai patients. 1946 40

Alterations of DNA methylation patterns have been suggested as biomarkers for diagnostics and therapy of cancers. Every novel discovery in the epigenetic landscape and every development of an improved approach for accurate analysis of the events may offer new opportunity for the management of patients. Using a novel high-throughput mass spectrometry on matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) silico-chips, we determined semiquantitative methylation changes of 22 candidate genes in breast cancer tissues. For the first time we analysed the methylation status of a total of 42 528 CpG dinucleotides on 22 genes in 96 different paraffin-embedded tissues (48 breast cancerous tissues and 48 paired normal tissues). A two-way hierarchical cluster analysis was used to classify methylation profiles. In this study, 10 hypermethylated genes (APC, BIN1, BMP6, BRCA1, CST6, ESRb, GSTP1, P16, P21 and TIMP3) were identified to distinguish between cancerous and normal tissues according to the extent of methylation. Individual assessment of the methylation status for each CpG dinucleotide indicated that cytosine hypermethylation in the cancerous tissue samples was mostly located near the consensus sequences of the transcription factor binding sites. These hypermethylated genes may serve as biomarkers for clinical molecular diagnosis and targeted treatments of patients with breast cancer.
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PMID:Methylation profiles of 22 candidate genes in breast cancer using high-throughput MALDI-TOF mass array. 1950 99

Cyclophosphamide (CPA)-based combination treatment has known to be effective for breast cancer, but often causes adverse drug reactions (ADRs). Hence, the identification of patients at risk for toxicity by CPA is clinically significant. In this study, a stepwise case-control association study was conducted using 403 patients with breast cancer who received the CPA combination therapy. A total of 143 genetic polymorphisms in 13 candidate genes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, ALDH1A1, ALDH3A1, GSTA1, GSTM1, GSTP1, GSTT1, ABCC2 and ABCC4), possibly involved in the activation, metabolism and transport of CPA, were genotyped using 184 cases who developed either > or =grade 3 leukopenia/neutropenia or > or =grade 2 gastrointestinal toxicity and 219 controls who did not show any ADRs throughout the treatment. The association study revealed that one SNP, rs9561778 in ABCC4, showed a significant association with CPA-induced ADRs (Cochran-Armitage trend's P-value=0.00031; odds ratio (OR)=2.06). Subgroup analysis also indicated that the SNP rs9561778 was significantly associated with two major ADR subgroups; gastrointestinal toxicity and leukopenia/neutropenia (Cochran-Armitage trend's P-value=0.00019 and 0.014; OR=2.31 and 1.83). Furthermore, the SNP rs9561778 showed an association with breast cancer patients who were treated with CA(F) drug regimen-induced ADR (Cochran-Armitage trend's P-value=0.00028; OR=3.13). The SNPs in ABCC4 might be applicable in predicting the risk of ADRs in patients receiving CPA combination chemotherapy.
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PMID:Association study of genetic polymorphism in ABCC4 with cyclophosphamide-induced adverse drug reactions in breast cancer patients. 1969 93

Cytosolic glutathione S-transferase comprises multiple isoenzymes; studies have principally examined mu-1 (GSTM1: null/present), theta-1 (GSTT1: null/present) and pi-1 (GSTP1 Ile105Val) gene polymorphisms concerning breast cancer risk. Regarding GSTT1 and GSTP1 polymorphisms, studies remain controversial and no recent meta-analysis has appeared. This meta-analysis aims to examine whether GSTT1 and GSTP1 polymorphisms are associated with breast cancer risk. Separate analyses were performed on Chinese and non-Chinese populations, in an attempt to investigate race-specific effects. Eligible articles were identified by a search of MEDLINE bibliographic database for the period up to August 2009. Regarding GSTT1 null/present genotype, 41 case-control studies were eligible (16,589 breast cancer cases and 19,995 controls); 30 case-control studies were eligible for GSTP1 Ile105Val (16,908 cases and 20,016 controls). Pooled odds ratios (ORs) were appropriately derived from fixed-effects or random-effects models. At the overall analysis, the null GSTT1 genotype was associated with elevated breast cancer risk (pooled OR = 1.114, 95% CI: 1.035-1.199, random effects). However, the association seemed confined to non-Chinese populations (33 studies, pooled OR = 1.128, 95% CI: 1.042-1.221, random effects), given that the association was not significant in the subset of Chinese studies (eight studies, pooled OR = 1.061, 95% CI: 0.875-1.286, random effects). Regarding GSTP1 Ile105Val, no statistically significant associations were detected in non-Chinese populations (25 studies). On the other hand, the GG genotype was associated with increased breast cancer risk in Chinese populations (five studies, pooled OR = 1.297, 95% CI: 1.023-1.645, fixed effects); accordingly, the recessive model yielded statistically significant results (pooled OR = 1.273, 95% CI: 1.006-1.610, fixed effects). In conclusion, polymorphisms of both GSTT1 and GSTP1 genes seem associated with elevated breast cancer risk in a race-specific manner. Given the small number of Chinese studies, the finding on GSTP1 Ile105Val merits further investigation.
Breast Cancer Res Treat 2010 May
PMID:GSTT1 and GSTP1 polymorphisms and breast cancer risk: a meta-analysis. 1976 40


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