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)

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is associated with mammary carcinomas in animals and humans. PhIP is metabolized by CYP 1A1/1A2 and cytochrome b5 reductase, producing free radicals causing DNA strand breaks. Diallyl sulfide (DAS) prevents cancer in animals. We hypothesized that DAS will attenuate PhIP-induced DNA strand breaks and cell death. To test this hypothesis, we treated MCF-10A cells with PhIP, DAS and PhIP/DAS for 24, 48 and 72 h. DAS inhibited the PhIP-induced DNA strand breaks by 22% after 48 h and the strand breaks were completely inhibited at 72 h. PhIP reduced cell viability at each time point. However, DAS only attenuated this reduction in cell viability by 56% at 72 h. N-OH PhIP inhibited cell viability by 26% at 72 h. DAS completely attenuated this reduction in cell viability and may prevent PhIP-induced breast cancer via alterations in DNA damage and cell viability.
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PMID:Diallyl sulfide inhibits PhIP-induced cell death via the inhibition of DNA strand breaks in normal human breast epithelial cells. 1863 92

Cytochrome P450 (CYP) 1A1 and CYP1B1 are inducible by 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) in the human breast cancer cell line, MCF-7. Since CYP1A1 was inducible to a much greater degree than CYP1B1, we hypothesized that there may be differences in coactivator recruitment to the promoter and/or enhancer regions of these genes. Dioxin treatment leads to recruitment of the aryl hydrocarbon receptor to the enhancer regions but not to the proximal promoter regions of both the CYP1A1 and CYP1B1 genes. On the other hand, dioxin treatment facilitated recruitment of RNA polymerase II to the promoters but not the enhancer regions. Dioxin treatment also elicited recruitment of the transcriptional coactivators, steroid receptor coactivator 1 (SRC-1) and steroid receptor coactivator 2 (SRC-2) and p300, which possess intrinsic histone acetyltranferase activities, to both genes, whereas Brahma (BRM)/Switch 2-related gene 1 (BRG-1), a subunit of nucleosomal remodeling factors, was recruited more robustly to CYP1A1 relative to CYP1B1. Small inhibitory RNA-mediated knockdown of p300 and SRC-2 adversely affected dioxin induction of both genes, whereas knockdown of BRM/BRG-1 reduced CYP1A1 induction but had little, if any, effect on CYP1B1 induction. These results suggest that nucleosomal remodeling is less significant for dioxin-mediated induction of CYP1B1 than that of CYP1A1 and may be related to the more modest inducibility of the former. Interestingly, simultaneous knockdown of SRC-2 and BRM/BRG-1 had no greater effect on CYP1A1 induction than knockdown of each coactivator individually, while simultaneous knockdown of p300 and BRM/BRG-1 had a much greater effect than knockdown of each individual gene, suggesting that the recruitment of SRC-2 to CYP1A1 depends upon BRM/BRG-1, while the recruitments of p300 and BRM/BRG-1 are independent of each other. These observations provide novel insights into the functional roles of the endogenous coactivators in dioxin induction of the human CYP1A1 and CYP1B1 genes in their natural chromosomal configurations.
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PMID:Roles of coactivator proteins in dioxin induction of CYP1A1 and CYP1B1 in human breast cancer cells. 1884 20

Genetic variability in drugmetabolizing enzymes affects the toxicity and efficacy of many compounds, including the chemotherapeutic agents irinotecan and tamoxifen. The correlation of clinical response to polymorphisms in enzymes associated with metabolism of these two drugs has led to the recommendation that patients who receive them undergo genotyping analysis. Irinotecan toxicity in patients who have colorectal cancer has been linked to reduced activity of uridine diphosphate-glucuronyltransferase 1A1 (UGT1A1). Reduced cytochrome P450 (CYP) 2D6 activity leads to therapeutic failure of tamoxifen in the prevention and treatment of breast cancer, as a result of absence of conversion of the prodrug to its active forms. This article discusses current knowledge of the usefulness of UGT1A1 and CYP2D6 genotyping in the context of cancer chemotherapy and highlights the need for additional studies to clarify the many issues remaining.
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PMID:Pharmacogenomics of tamoxifen and irinotecan therapies. 1905 62

Southeast Asian women have a lower incidence of breast cancer than their counterparts in the West. Epidemiological studies have indicated that soya consumption may be a contributing factor. Carcinogenesis is a process involving multiple stages. The present review attempts to fit the cellular mechanisms attributed to soya isoflavones into these different stages. Many cell-culture studies have reported the growth-inhibitory effect of soya isoflavones; however, with the non-physiological concentrations employed in these studies it would be difficult to explain the protection mechanisms observed in epidemiological studies. Our laboratory has previously found that genistein inhibits cytochrome P450 (CYP)1A1 and CYP1B1. The inhibition implies that soya consumption may have the potential to prevent chemical carcinogenesis. The preferential inhibition of CYP1B1 may also block the oestrogen-initiated carcinogenesis. The antagonism of oestrogen receptor (ER) binding can affect the cell-proliferative phase, which is likely to be important in the promotion stage of breast cancer. Since our laboratory and others have indicated that genistein at physiological concentrations has no effect on the downstream activities of ER binding, the antagonism of ER is not likely to be a contributing factor in the disease prevention. Moreover, soya isoflavones cannot inhibit aromatase (CYP19), which is the enzyme responsible for oestrogen synthesis. In the present review various cellular activities altered by soya isoflavones are discussed.
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PMID:Dietary soya isoflavones and breast carcinogenesis: a perspective from a cell-culture model. 1907 5

Selective estrogen receptor (ER) modulators are used as a therapy for ER+ clinical breast cancer, but they exhibit adverse effects. Herbal medicines may provide an alternative or complementary approach. Taheebo, extracted from the inner bark of the Tabebuia avellandae tree found in the Brazilian Amazon, exhibits selective anti-proliferative effects in carcinoma cell lines. The present study identifies the mechanistic leads for the inhibitory effects of Taheebo. Human breast carcinoma derived ER+MCF-7 cells were used as the model. Aqueous extract of Taheebo was the test compound. Cell cycle analysis, clonogenic assay, and global gene expression profiles were the quantitative parameters. Taheebo treatment resulted in a dose/time-dependent growth inhibition (S phase arrest, reduced clonogeneticity) and initiation of apoptosis (chromatin condensation). A 6-h treatment with 1.5 mg/ml Taheebo modulated the gene expression of G2 specific cyclin B1 (-2.0-fold); S phase specific PCNA (-2.0-fold) and OKL38 (+11.0-fold); apoptosis specific GADD-45 family (+1.9-5.4-fold), Caspases (+1.6-1.7-fold), BCL-2 family (-1.5-2.5-fold), estrogen responsive ESR1 (-1.5-fold), and xeno-biotic metabolism specific CYP 1A1 (+19.8 fold) and CYP 1B1 (+7.9-fold). The anti-proliferative effects of Taheebo correlate with down-regulated cell cycle regulatory and estrogen responsive genes, and up-regulated apoptosis specific and xeno-biotic metabolism specific genes. These data validate a rapid mechanistic approach to prioritize efficacious herbal medicines, thereby complementing the existing endocrine therapy for breast cancer.
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PMID:Growth inhibition of estrogen receptor positive human breast cancer cells by Taheebo from the inner bark of Tabebuia avellandae tree. 1957 98

Estrogen is a well-known risk factor for breast cancer. Current models of breast cancer risk prediction are based on cumulative estrogen exposure but do not directly reflect mammary estrogen metabolism or address genetic variability between women in exposure to carcinogenic estrogen metabolites. We are proposing a mathematical model that forecasts breast cancer risk for a woman based on three factors: (1) estimated estrogen exposure, (2) kinetic analysis of the oxidative estrogen metabolism pathway in the breast, and (3) enzyme genotypes responsible for inherited differences in the production of carcinogenic metabolites. The model incorporates the main components of mammary estrogen metabolism, i.e. the conversion of 17beta-estradiol (E(2)) by the phase I and II enzymes cytochrome P450 (CYP) 1A1 and 1B1, catechol-O-methyltransferase (COMT), and glutathione S-transferase P1 (GSTP1) into reactive metabolites, including catechol estrogens and estrogen quinones, such as E(2)-3,4-Q which can damage DNA. Each of the four genes is genotyped and the SNP data used to derive the haplotype configuration for each subject. The model then utilizes the kinetic and genotypic data to calculate the amount of E(2)-3,4-Q carcinogen as ultimate risk factor for each woman. The proposed model extends existing models by combining the traditional "phenotypic" measures of estrogen exposure with genotypic data associated with the metabolic fate of E(2) as determined by critical phase I and II enzymes. Instead of providing a general risk estimate our model would predict the risk for each individual woman based on her age, reproductive experiences as well as her genotypic profile.
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PMID:Estrogen exposure, metabolism, and enzyme variants in a model for breast cancer risk prediction. 1971 49

A 17beta-estradiol (E(2)) is hydrolyzed to 2-hydroxy-E(2) (2-OHE(2)) and 4-hydroxy-E(2) (4-OHE(2)) via cytochrome P450 (CYP) 1A1 and 1B1, respectively. In estrogen target tissues including the mammary gland, ovaries, and uterus, CYP1B1 is highly expressed, and 4-OHE(2) is predominantly formed in cancerous tissues. In this study, we investigated the inhibitory effects of chrysoeriol (luteorin-3'-methoxy ether), which is a natural methoxyflavonoid, against activity of CYP1A1 and 1B1 using in vitro and cultured cell techniques. Chrysoeriol selectively inhibited human recombinant CYP1B1-mediated 7-ethoxyresorufin-O-deethylation (EROD) activity 5-fold more than that of CYP1A1-mediated activity in a competitive manner. Additionally, chrysoeriol inhibited E(2) hydroxylation was catalyzed by CYP1B1, but not by CYP1A1. Methylation of 4-OHE(2), which is thought to be a detoxification process, was not affected by the presence of chrysoeriol. In human breast cancer MCF-7 cells, chrysoeriol did not affect the gene expression of CYP1A1 and 1B1, but significantly inhibited the formation of 4-methoxy E(2) without any effects on the formation of 2-methoxy E(2). In conclusion, we present the first report to show that chrysoeriol is a chemopreventive natural ingredient that can selectively inhibit CYP1B1 activity and prevent the formation of carcinogenic 4-OHE(2) from E(2.).
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PMID:A methoxyflavonoid, chrysoeriol, selectively inhibits the formation of a carcinogenic estrogen metabolite in MCF-7 breast cancer cells. 1983 5

Uridine diphospho-glucuronosyltransferase 1A1 (UGT1A1) plays an important role in breast cancer development. To date, many publications have evaluated the correlation between UGT1A1 TA-repeat polymorphism and breast cancer risk. However, the results remain inconclusive. In order to resolve this conflict, a meta-analysis was performed by searching Medline, PubMed, and ISI Web of Knowledge databases. Seven studies including 5,746 cases and 8,365 controls were collected for UGT1A1 TA-repeat polymorphism. The strength of association between UGT1A1 TA-repeat polymorphism and breast cancer risk was assessed by calculating crude ORs with 95% CIs. Overall, no significant associations between UGT1A1 TA-repeat polymorphism and breast cancer susceptibility were found. In the stratified analysis by ethnicity and source of controls, significant associations were only observed for 6/6 versus 7/7 (OR = 0.88; 95% CI: 0.77-0.99; P = 0.425 for heterogeneity) in Caucasians, but no in other genetic models. In conclusion, this meta-analysis suggests that UGT1A1 A(TA)(7)TAA allele is a potential risk factor for breast cancer in Caucasians.
Breast Cancer Res Treat 2010 Aug
PMID:The association between TA-repeat polymorphism in the promoter region of UGT1A1 and breast cancer risk: a meta-analysis. 2008 47

Cytochrome P450 (CYP) 1B1 catalyzes 17beta-estradiol (E(2)) to predominantly carcinogenic 4-hydroxy-E(2), whereas CYP1A1 and 1A2 convert E(2) to non-carcinogenic 2-hydroxy-E(2). Hence, selective inhibition of CYP1B1 is recognized to be beneficial for the prevention of E(2) related breast cancer. In this study, we first evaluated the structure-property relationship of 18 major flavonoids on inhibiting enzymatic activity of CYP1A1, 1A2 and 1B1 by using an ethoxyresorufin O-deethylation assay. Flavones and flavonols indicated relatively strong inhibitory effects on CYP1s compared with flavanone that does not have the double bond between C-positions 2 and 3 on the C-ring. Flavonoids used in this study selectively inhibited CYP1B1 activity. In particular, methoxy types of flavones and flavonols such as chrysoeriol and isorhamnetin showed strong and selective inhibition against CYP1B1. To understand why selective inhibition was observed, we carried out a molecular docking analysis of these methoxyflavonoids with the 2-3 double bond and CYP1s. The results suggested that chrysoeriol and isorhamnetin fit well into the active site of CYP1B1, but do not fit into the active site of CYP1A2 and 1A1 because of steric collisions between the methoxy substituent of these methoxyflavonoids and Ser-122 in CYP1A1 and Thr-124 in CYP1A2. In conclusion, our results demonstrate: (1) strong inhibitory effects of flavonoids on CYP1 activities require the 2-3 double bond on the C-ring; (2) methoxyflavonoids with the 2-3 double bond had strong and selective inhibition against CYP1B1, suggesting chemopreventive flavonoids for E(2) related breast cancer; and (3) binding specificity of these methoxyflavonoids is based on the interactions between the methoxy groups and specific CYP1s residues.
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PMID:Selective inhibition of methoxyflavonoids on human CYP1B1 activity. 2069 80

In the last few years, significant advances have been made toward understanding the joint action of endocrine disrupting chemicals (EDCs). A number of studies have demonstrated that the combined effects of different types of EDCs (e.g., estrogenic, antiandrogenic, or thyroid-disrupting agents) can be predicted by the model of concentration addition (CA). However, there is still limited information on the effects of mixtures of large numbers of chemicals with varied structural features, which are more representative of realistic human exposure scenarios. The work presented here aims at filling this gap. Using a breast cancer cell proliferation assay (E-Screen), we assessed the joint effects of five mixtures, containing between 3 and 16 estrogenic agents, including compounds as diverse as steroidal hormones (endogenous and synthetic), pesticides, cosmetic additives, and phytoestrogens. CA was employed to predict mixture effects, which were then compared with experimental outcomes. The effects of two of the mixtures tested were additive, being accurately predicted by CA. However, for the three other mixtures, CA slightly overestimated the experimental observations. In view of these results, we hypothesized that the deviations were due to increased metabolism of steroidal estrogens in the mixture setting. We investigated this by testing the impact of two such mixtures on the activation and expression of steroidal estrogen metabolizing enzymes, such as cytochrome P450 (CYP) 1A1, CYP 1B1, and CYP 3A4. Activation of CYP 1B1 and, consequently, a reduction in the levels of steroidal estrogens in the mixture could contribute to the shortfall from the additivity prediction that we observed.
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PMID:Joint effects of heterogeneous estrogenic chemicals in the E-screen--exploring the applicability of concentration addition. 2156 85


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