UMLS:C0006142 - FACTA Search

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Query: UMLS:C0006142 (breast cancer)
160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cataract is the leading cause of visual impairment in older adults in the world. Age-related lens opacities are common and are frequent causes of loss of vision. The incidence of cataract increases significantly with increasing age in women only. The onset coincides with estrogen deficiency that occurs after menopause. Hormone replacement therapy has proven beneficial to selected postmenopausal women. Estrogen effects on biological system are modulated via the estrogen receptors (ER) and/or estrogen metabolites. Although ER have been detected in ocular tissue, whether ER polymorphism is related to cataract is not known at present. The polymorphisms of estrogen metabolizing enzymes are also related to the serum concentration and activity of estrogen. Polymorphism such as cytochrome P450c17 (A2/A2), cytochrome P450c1A (vt/vt) will result in increased formation of catechol estrogen, while people with catechol-O-methyltransferase (COMT) polymorphism COMT (L/L) will have decreased metabolism of catechol estrogen and decreased level of methoxyestradiol. COMT was also involved in tamoxifen metabolism which may further decrease the activity of COMT in breast cancer patients treated with tamoxifen. It is known that a 4-7% increase in cataract was found in tamoxifen-treated breast cancer patients than non-user. The 7.0% COMT (L/L) genotype in general population corresponded well with the 4-7% of cataract formation in tamoxifen-treated breast cancer patients. Our hypothesis is that breast cancer patients with COMT (L/L) genotype may be at increased risk of cataract formation after tamoxifen treatment.
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PMID:Polymorphism of estrogen metabolism genes and cataract. 1528 75

Estrogens and their oxidative metabolites, the catechol estrogens, have been implicated in the development of breast cancer; yet, relatively little is known about estrogen metabolism in the breast. To determine how the parent hormone, 17 beta-estradiol (E(2)), is metabolized, we used recombinant, purified phase I enzymes, cytochrome P450 (CYP) 1A1 and 1B1, with the phase II enzymes catechol-O-methyltransferase (COMT) and glutathione S-transferase P1 (GSTP1), all of which are expressed in breast tissue. We employed both gas and liquid chromatography with mass spectrometry to measure E(2), the catechol estrogens 2-hydroxyestradiol (2-OHE(2)) and 4-hydroxyestradiol (4-OHE(2)), as well as methoxyestrogens and estrogen-GSH conjugates. The oxidation of E(2) to 2-OHE(2) and 4-OHE(2) was exclusively regulated by CYP1A1 and 1B1, regardless of the presence or concentration of COMT and GSTP1. COMT generated two products, 2-methoxyestradiol and 2-hydroxy-3-methoxyestradiol, from 2-OHE(2) but only one product, 4-methoxyestradiol, from 4-OHE(2). Similarly, GSTP1 yielded two conjugates, 2-OHE(2)-1-SG and 2-OHE(2)-4-SG, from the corresponding quinone 2-hydroxyestradiol-quinone and one conjugate, 4-OHE(2)-2-SG, from 4-hydroxyestradiol-quinone. Using the experimental data, we developed a multicompartment kinetic model for the oxidative metabolism of the parent hormone E(2), which revealed significant differences in rate constants for its C-2 and C-4 metabolites. The results demonstrated a tightly regulated interaction of phase I and phase II enzymes, in which the latter decreased the concentration of catechol estrogens and estrogen quinones, thereby reducing the potential of these oxidative estrogen metabolites to induce DNA damage.
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PMID:In vitro model of mammary estrogen metabolism: structural and kinetic differences between catechol estrogens 2- and 4-hydroxyestradiol. 1537 60

Estrogen has been suggested to trigger breast cancer development via an initiating mechanism involving its metabolite, catechol estrogen (CE). To examine this hypothesis, we carried out a multigenic case-control study of 469 incident breast cancer patients and 740 healthy controls to define the role of important genes involved in the different metabolic steps that protect against the potentially harmful effects of CE metabolism. We studied the 3 genes involved in CE detoxification by conjugation reactions involving methylation (catechol-O-methyltransferase, COMT), sulfation (sulfotransferase 1A1, SULT1A1), or glucuronidation (UDP-glucuronosyltransferase 1A1, UGT1A1), one (manganese superoxide dismutase, MnSOD) involved in protection against reactive oxidative species-mediated oxidation during the conversion of CE-semiquinone (CE-SQ) to CE-quinone (CE-Q), and 2 of the glutathione S-transferase superfamily, GSTM1 and GSTT1, involved in CE-Q metabolism. Support for this hypothesis came from the observations that (i) there was a trend toward an increased risk of breast cancer in women harboring a greater number of putative high-risk genotypes of these genes (p < 0.05); (ii) this association was stronger and more significant in those women who were more susceptible to estrogen [no history of pregnancy or older (> or =26 years) at first full-term pregnancy (FFTP)]; and (iii) the risks associated with having one or more high-risk genotypes were not the same in women having experienced different menarche-to-FFTP intervals, being more significant in women having been exposed to estrogen for a longer period (> or =12 years) before FFTP. Furthermore, because CE-Q can attack DNA, leading to the formation of double-strand breaks (DSB), we examined whether the relationship between cancer risk and the genotypic polymorphism of CE-metabolizing genes was modified by the genotypes of DSB repair genes, and found that a joint effect of CE-metabolizing genes and one of the two DSB repair pathways, the homologous recombination pathway, was significantly associated with breast cancer development. Based on comprehensive CE metabolizing gene profiles, our study provides support to the hypotheses that breast cancer can be initiated by estrogen exposure and that increased estrogen exposure confers a higher risk of breast cancer by causing DSB to DNA.
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PMID:Breast cancer risk associated with genotype polymorphism of the catechol estrogen-metabolizing genes: a multigenic study on cancer susceptibility. 1545 71

The role of tea in the etiology of breast cancer is controversial. We recently provided the first set of human evidence that breast cancer risk is significantly inversely associated with tea intake, largely confined to intake of green tea. Since black tea and green tea possess comparable levels of the total tea polyphenols that possess antioxidative activities, reasons for the paradoxical effects of green tea and black tea on breast cancer protection are not apparent. Some limited evidence suggests that green tea may have downregulatory effects on circulating sex-steroid hormones, whereas black tea may have upregulatory effects. We therefore, investigated the relationship between tea intake, and plasma estrogen and androstenedione levels in a cross-sectional study of healthy postmenopausal Chinese women in Singapore. In this group of 130 women, 84 were non or irregular (less than once a week) tea drinkers, 27 were regular (weekly/daily) green tea drinkers and 19 were regular (weekly/daily) black tea drinkers. Relative to plasma estrone levels in non- or irregular tea drinkers (29.5 pg/ml) the levels were 13% lower in regular green tea drinkers (25.8 pg/ml) and 19% higher in regular black tea drinkers (35.0 pg/ml). These differences in estrone levels were statistically significant (P = 0.03) inspite of adjusting for age, body mass index, intake of soy, and other covariates. A similar pattern of differences between tea intake, and plasma levels of estradiol (P = 0.08) and androstenedione (P = 0.14) were found. In addition, the tea-estrogen associations were observed irrespective of the genotype of catechol-O-methyltransferase (COMT), a major enzyme that aids in the excretion of tea polyphenols in humans. Larger studies are needed to confirm results from this cross-sectional study and to better understand the potentially differing effect of black and green tea on circulating estrogen levels and ultimately on the risk of breast cancer.
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PMID:Tea and circulating estrogen levels in postmenopausal Chinese women in Singapore. 1566 1

Cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) are important estrogen-metabolizing enzymes and, thus, genetic polymorphisms of these enzymes may affect breast cancer risk. A population-based case-control study was conducted to assess the association of breast cancer risk with CYP1B1 and COMT polymorphisms. A meta-analysis was done to summarize the findings from this and previous studies. Included in this study were 1,135 incident breast cancer cases diagnosed from August 1996 through March 1998 among female residents of Shanghai and 1,235 randomly selected, age frequency-matched controls from the same general population. The common alleles of the CYP1B1 gene were Arg (79.97%) in codon 48, Ala (80.53%) in codon 119, and Leu (86.57%) in codon 432. The Val allele accounted for 72.46% of the total alleles identified in codon 108/158 of the COMT gene. No overall associations of breast cancer risk were found with any of the single nucleotide polymorphisms described above. This finding was supported by a meta-analysis of all previous published studies. No gene-gene interactions were observed between CYP1B1 and COMT genotypes. The associations of breast cancer risk with factors related to endogenous estrogen exposure, such as years of menstruation and body mass index, were not significantly modified by the CYP1B1 and COMT genotypes. We observed, however, that women who carried one copy of the variant allele in CYP1B1 codons 48 or 119 were less likely to have estrogen receptor-positive breast cancer than those who carried two copies of the corresponding wild-type alleles. The results from this study were consistent with those from most previous studies, indicating no major associations of breast cancer risk with CYP1B1 and COMT polymorphisms.
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PMID:Cytochrome P450 1B1 and catechol-O-methyltransferase genetic polymorphisms and breast cancer risk in Chinese women: results from the shanghai breast cancer study and a meta-analysis. 1573 54

This nested case-control study evaluated the role of polymorphisms in the myeloperoxidase (MPO) and catechol-O-methyltransferase (COMT) genes that modulate oxidative stress in breast cancer risk in a Chinese population. Our results demonstrate that the MPO A/A genotype was associated with a reduced risk of breast cancer (odds ratio (OR) 0.64; 95% confidence interval (CI) 0.11-3.76), whereas there was no overall association of COMT genotype with breast cancer. Of note, an elevated breast cancer risk associated with the increasing numbers of high-risk genotypes of MPO and COMT genes was observed in women with a longer duration between menarche and first full-term pregnancy.
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PMID:Genetic variants of myeloperoxidase and catechol-O-methyltransferase and breast cancer risk. 1590 95

Polymorphic catechol-O-methyltransferase (COMT) catalyzes the O-methylation of catechol estrogens. It has been reported that COMT polymorphism is a representative genetic trait related to the susceptibility of an individual to breast cancer. However, there is no consensus concerning the association between breast cancer in Japanese patients and COMT polymorphism. To analyze the polymorphism distribution in Japanese patients with breast cancer, a molecular genotyping method using a polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) was used. Based on an analysis of 201 Japanese patients with breast cancer and 352 healthy control subjects, a significant difference was observed in either the distribution of genotypes (p=0.03) or allele frequencies between the two groups (p=0.01). The relative risk of breast cancer for genotypes (COMT(Met/Met) and COMT(Val/Met)) including the variant allele (COMT(Met)) was 1.47 compared to the wild allele (COMT(Val)) and homozygote (COMT(Val/Val)). Furthermore, the distribution of genotypes in post-menopausal patients with breast cancer showed a significant difference with that of healthy subjects of the same menopausal status (p=0.01). No significant difference was found between the distribution of genotypes and clinicopathological features of the cancer. These results suggest that COMT polymorphism may thus be implicated as a genetic trait affecting the susceptibility of an individual to breast cancer in a Japanese population and be an important genetic risk factor in the development of breast cancer in post-menopausal women.
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PMID:Genetic susceptibility of catechol-O-methyltransferase polymorphism in Japanese patients with breast cancer. 1607 79

We studied the modulating effects of caffeic acid and chlorogenic acid (two common coffee polyphenols) on the in vitro methylation of synthetic DNA substrates and also on the methylation status of the promoter region of a representative gene in two human cancer cells lines. Under conditions that were suitable for the in vitro enzymatic methylation of DNA and dietary catechols, we found that the presence of caffeic acid or chlorogenic acid inhibited in a concentration-dependent manner the DNA methylation catalyzed by prokaryotic M.SssI DNA methyltransferase (DNMT) and human DNMT1. The IC50 values of caffeic acid and chlorogenic acid were 3.0 and 0.75 microM, respectively, for the inhibition of M.SssI DNMT-mediated DNA methylation, and were 2.3 and 0.9 microM, respectively, for the inhibition of human DNMT1-mediated DNA methylation. The maximal in vitro inhibition of DNA methylation was approximately 80% when the highest concentration (20 microM) of caffeic acid or chlorogenic acid was tested. Kinetic analyses showed that DNA methylation catalyzed by M.SssI DNMT or human DNMT1 followed the Michaelis-Menten curve patterns. The presence of caffeic acid or chlorogenic acid inhibited DNA methylation predominantly through a non-competitive mechanism, and this inhibition was largely due to the increased formation of S-adenosyl-L-homocysteine (SAH, a potent inhibitor of DNA methylation), resulting from the catechol-O-methyltransferase (COMT)-mediated O-methylation of these dietary catechols. Using cultured MCF-7 and MAD-MB-231 human breast cancer cells, we also demonstrated that treatment of these cells with caffeic acid or chlorogenic acid partially inhibited the methylation of the promoter region of the RARbeta gene. The findings of our present study provide a general mechanistic basis for the notion that a variety of dietary catechols can function as inhibitors of DNA methylation through increased formation of SAH during the COMT-mediated O-methylation of these dietary chemicals.
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PMID:Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols. 1608 10

Estrogens are a known risk factor for breast cancer. Studies indicate that initiation of breast cancer may occur by metabolism of estrogens to form abnormally high levels of catechol estrogen-3,4-quinones, which can then react with DNA to form depurinating adducts and, subsequently, induce mutations that lead to cancer. Among the key enzymes metabolizing estrogens are two activating enzymes: cytochrome P450 (CYP)19 (aromatase), which converts androgens to estrogens, and CYP1B1, which converts estrogens predominantly to the 4-catechol estrogens that are further oxidized to catechol estrogen-3,4-quinones. Formation of the quinones is prevented by methylation of the 4-catechol estrogens by the enzyme, catechol-O-methyltransferase (COMT). In addition, catechol estrogen quinones can be reduced back to catechol estrogens by NADPH quinone oxidoreductase 1 (NQO1) and/or are coupled with glutathione, preventing reaction with DNA. Thus, COMT and NQO1 are key deactivating enzymes. In this initial study, we examined whether the expression of these four critical estrogen activating/deactivating enzymes is altered in breast cancer. Control breast tissue was obtained from four women who underwent reduction mammoplasty. Breast tissues from five women with breast carcinoma, who underwent mastectomy, were used as cases. The level of expression of CYP19, CYP1B1, COMT and NQO1 mRNAs was quantified from total RNA using a real time RT-PCR method in an ABI PRISM 7700 sequence detection system. The control breast tissues showed lower expression of the activating enzymes, CYP19 and CYP1B1, and higher expression of the deactivating enzymes, COMT and NQO1, compared to the cases. In the cases, the reverse pattern was observed: greater expression of activating enzymes and lower expression of deactivating enzymes. Thus, in women with breast cancer, estrogen metabolism may be related to altered expression of multiple genes. These unbalances appear to be instrumental in causing excessive formation of catechol estrogen quinones that, by reacting with DNA, initiate the series of events leading to breast cancer.
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PMID:Relative imbalances in the expression of estrogen-metabolizing enzymes in the breast tissue of women with breast carcinoma. 1614 78

The gene encoding catechol-O-methyltransferase (COMT), critical to the inactivation of reactive catechol estrogens, has several single nucleotide polymorphisms (SNPs) that influence enzyme activity. A 3-SNP haplotype (IVS1+255 C>T; Ex4-12 G>A; 3'UTR-521 A>G), which has been shown to reduce COMT expression in the human brain, has been identified. To evaluate the influence of genetic variation of COMT on breast cancer risk, these 3-SNPs were genotyped in 1052 cases and 1098 controls. We estimated the associations between breast cancer and individual SNPs, as well as, multilocus haplotypes. We also examined surrogates of hormone exposure as potential modifiers of the putatively functional Ex4-12 SNP-breast cancer association. Odds ratios (OR) and 95% confidence intervals (CI) were based on age-adjusted unconditional logistic regression models. We found no association between the individual SNPs alone and breast cancer. When examining the association between breast cancer and the 3-SNP haplotypes, we observed a 19% increase in risk associated with each copy of the TGG haplotype (OR=1.19, 95% CI 0.96-1.49), relative to the common TAA haplotype, which was statistically significant when assuming a dominant model (OR=1.32, 95% CI 1.05-1.67, p-value=0.02). In this report of COMT haplotypes and breast cancer, we found some evidence that additional genetic variability beyond the Ex4-12 G>A SNP contributes to risk of breast cancer among a small subgroup of women; however, these results need to be replicated in additional studies.
Breast Cancer Res Treat 2006 Sep
PMID:Catechol-O-methyltransferase haplotypes and breast cancer among women on Long Island, New York. 1659 27

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