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)

Advanced breast cancer responds to a range of cytotoxic agents, but resistance always develops. Understanding the mechanisms of resistance may provide new therapeutic options. There are several major groups of resistance mechanisms. 1) The multidrug resistant phenotype. This is due to a membrane pump that can extrude a wide range of anticancer drugs--the P-glycoprotein. It is inhibited by a range of clinically used calcium channel blockers such as nifedipine and verapamil. Several other membrane proteins of 180 KD, 170 KD, 300 KD and 85 KD have been reported and are associated with MDR. 2) Glutathione transferences and detoxification mechanisms. These are a multigene family of enzymes that conjugate glutathione to chemically reactive groups. There are 3 major groups of enzymes--acidic, basic and neutral. They have been implicated in resistance to doxorubicin, melphalan cisplatinum chlorambucil and other alkylating agents. Other protecting systems include metallothionein and selenium dependent glutathione peroxidase. HSP27 confers doxorubicin resistance. 3) Topoisomerase II. DNA topoisomerases are involved in several aspects of DNA metabolism in particular genetic recombination, DNA transcription, chromosome segregation. They are a target for doxorubicin, mitoxantrone, VP16. Low levels of expression are associated with resistance. However, it is oestrogen inducible and this may be of therapeutic value. A novel topo IIb which is more drug resistant has been reported. 4) DNA repair. A score or more of genes are involved in the repair of DNA damage by drugs and radiation. Defective DNA repair may predispose to cancer of the breast and be responsible for adverse radiation reactions. Enhanced repair has been shown to be a mechanism of cisplatinum resistance. Several genes are inducible by DNA damage and may confer resistance e.g. A45. 5) Drug activation. Mitomycin C as well as cyclophosphamide and VP16 require activation for their effects. Low levels of cytochrome p450 reductase are associated with MMC resistance.
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PMID:Mechanisms of multidrug resistance in cancer treatment. 135 55

A mammalian cell expression plasmid containing cytochrome P450IIIA7 complementary DNA was constructed. Breast cancer cells (MCF-7) were transfected with the plasmid and neomycin-resistant selection marker plasmid. We established three cell lines, termed M13, M21, and M27, which expressed the cytochrome P450IIIA7 as examined by RNA blot and immunoblot analyses. These cell lines showed 8- to 10-fold higher sensitivity against aflatoxin B1 compared to parental MCF-7 cells, suggesting that cytochromes P450IIIA7 expressed in the cells were responsible for the production of the cytotoxic metabolite of aflatoxin B1.
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PMID:Stable expression of cytochrome P450IIIA7 cDNA in human breast cancer cell line MCF-7 and its application to cytotoxicity testing. 172 31

The synthesis of 3-(cyclohexymethyl)-1-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane-2, 4-dione (1h), with its optical enantiomers, and a series of novel achiral 1-(4-aminophenyl)-3-azabicyclo[3.1.1]haptane-2,4-diones (2a-i,k) is described. These compounds were tested in vitro for inhibition of human placental aromatase, a cytochrome-P450-dependent enzyme responsible for the conversion of androgens to estrogens. All of them displayed enzyme-inhibiting activity, and 3-cyclohexyl derivative 2g and 3-cyclohexylmethyl derivative 1h both proved more potent (greater than 140-fold) than the clinically effective agent aminoglutethimide [3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione, AG]. As with AG and its derivatives, the 1R-(+)-enantiomer of 1h was responsible for the enzyme inhibitory activity. These novel compounds are of interest as potential drugs for endocrine therapy of hormone-dependent tumors, e.g. breast cancer.
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PMID:Synthesis and aromatase inhibitory activity of novel 1-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane- and -[3.1.1]heptane-2,4- diones. 201 6

Acetone extracts of airborne particulates collected at different sites in the greater Copenhagen area were tested for their ability to induce the expression of cytochrome P-450IA1 RNA in a human breast cancer cell line, T47-D. The induction efficiency was expressed as an benz[a] anthracene equivalents, that is, the amount of benz[a]anthracene required to give the same level of induction. A significantly higher level of induction of P-450IA1 RNA was seen with samples collected on days with a smog alert. The inducibility of samples collected in rural areas was lower, but no significant difference in inducibility was found between samples collected in urban and suburban areas. Lack of correlation between the mutagenic activity in the Ames assay and the P-450IA1-inducing activity of the samples suggests that the complex mixture of compounds found in airborne particulates may have different biological activities in the two short-term test systems. Measurements of P-450IA1 inducibility provide a new, sensitive approach to assess the biological activity of material present in air pollution. The presence in airborne particulates of chemical compounds that induce cytochrome P-450IA1 an enzyme responsible for the metabolism of ubiquitous chemical carcinogens, suggests that the general environment may change an individual's response to the impact of exogenous chemicals, including the carcinogens present in cigarette smoke.
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PMID:Extracts of airborne particulates collected at different locations in the Copenhagen area induce the expression of cytochrome P-450IA1. 238 97

Multidrug resistance (MDR) in an MCF-7 human breast cancer cell line (MCF7/Adr) is associated with decreased drug accumulation and overexpression of P-glycoprotein as well as alterations in the levels of specific drug-metabolizing enzymes, including decreased activity of the phase I drug-metabolizing enzyme aryl hydrocarbon hydroxylase (AHH) and increased expression of the anionic form of the phase II drug-metabolizing enzyme glutathione S-transferase. Since the development of MDR in this MCF-7 cell line is also associated with a loss of estrogen receptors (ER), we have examined the expression of cytochrome P450IA 1, the gene encoding AHH activity, in other breast cancer cell lines not selected for drug resistance but expressing various levels of ER. These studies show that a relationship exists between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible AHH activity and the ER content in a series of breast cancer cell lines. In these cell lines expression of AHH activity is regulated, at least in part, at the level of P450IA 1 RNA. While TCDD-specific binding proteins (Ah receptors) were found in each of the breast cancer cell lines, there was no apparent relation between the level of nuclear TCDD-binding proteins and the level of TCDD-inducible P450IA 1 expression. Previous studies from our laboratory have described an inverse relationship between levels of the anionic form of glutathione S-transferase and ER in breast cancer.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Relation between cytochrome P450IA1 expression and estrogen receptor content of human breast cancer cells. 246 54

MCF-7 human breast cancer cells, selected for resistance to adriamycin (AdrR), exhibit the phenotype of multidrug resistance (MDR). Previous studies have shown that resistance in AdrR MCF-7 cells is associated with several biochemical changes that are similar to those induced in rat hyperplastic nodules, preneoplastic liver lesions which display broad spectrum resistance to carcinogens and hepatotoxins. In this report, we show that these changes in the AdrR MCF-7 cells are also associated with the development of cross-resistance to the procarcinogen benzo(a)pyrene (BP) and are associated with a marked defect in the conversion of BP to its cytotoxic, carcinogenic metabolites by AdrR cells. Since aryl hydrocarbon hydroxylase is the principle enzyme activity which converts benzo(a)pyrene to toxic hydroxylated forms, the regulation of cytochrome P-450IA1 expression, the gene encoding this enzyme activity in MCF-7 cells, was examined. Incubation with 100 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for 24 h results in a marked increase in aryl hydrocarbon hydroxylase activity in wild type (WT) but not AdrR MCF-7 cells. The alteration in aryl hydrocarbon hydroxylase expression in the AdrR cells is not overcome by incubation either with higher concentrations of TCDD (1 microM) or for longer periods of time (4 days). Northern blot analysis indicates that this defect in AdrR MCF-7 cells involves a regulatory defect at the level of P-450IA1 RNA. Following transfection of a construct containing the normal mouse P-450IA1 promoter fused to a reporter gene (bacterial chloramphenicol acetyltransferase) into WT and AdrR MCF-7 cells, TCDD induced chloramphenicol acetyltransferase activity in WT MCF-7 cells only. Furthermore, TCDD also induces both DT-diaphorase and UDP-glucuronyltransferase activities in WT, but not AdrR cells. These data suggest that the defect in the AdrR MCF-7 cells is not due to a structural P-450IA1 gene mutation, but rather involves a product regulating the polycyclic hydrocarbon-inducible expression of several drug-metabolizing enzyme activities. This defect in the AdrR MCF-7 cells is also associated with the development of resistance to ellipticine, an anticancer agent which is converted to more toxic hydroxylated species by aryl hydrocarbon hydroxylase or a similar mixed function oxidase. The WT and AdrR MCF-7 cells represent a useful model to study the regulation of the P-450IA1 gene in human cells.
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PMID:Altered regulation of P-450IA1 expression in a multidrug-resistant MCF-7 human breast cancer cell line. 314 24

MCF7 human breast cancer cells selected for resistance to doxorubicin (adriamycin; DoxR) have developed the phenotype of multidrug resistance. Multidrug resistance in DoxR MCF7 cells (called AdrR MCF7 cell line in previous publications) is associated with biochemical changes similar to those induced by carcinogens in rat hyperplastic liver nodules (HNs) and associated with resistance to xenobiotics in that system. In HNs and DoxR cells, exposure to a single agent results in the selection of cells that are cross-resistant to a wide variety of structurally dissimilar toxic agents. Resistance in both systems is associated with decreases in intracellular accumulation of toxins and changes in phase I (decreased cytochrome P1-450) and phase II (increased glutathione transferase and glucuronyltransferase) drug-metabolizing activities. In HNs and DoxR cells, resistance is associated with the induction of relatively stable levels of an immunologically related anionic glutathione transferase isozyme (EC 2.5.1.18). The finding of similar biochemical changes associated with the development of resistance to various xenobiotics in HNs and to many naturally occurring antineoplastic agents and at least one carcinogen (benzo[a]pyrene) in DoxR MCF7 cells suggests that the mechanisms of resistance in these two models may be similar.
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PMID:Similar biochemical changes associated with multidrug resistance in human breast cancer cells and carcinogen-induced resistance to xenobiotics in rats. 354 Sep 35

Polycyclic aromatic hydrocarbons, possible human breast carcinogens, are metabolized by cytochrome P4501A1 (CYP1A1) and glutathione S-transferase (GSTM1). A CYP1A1 polymorphism (isoleucine to valine substitution in exon 7) or the null allele for GSTM1 may affect the mutagenic potential of polycyclic aromatic hydrocarbons. We examined polymorphisms in GSTM1 and CYP1A1 in relation to breast cancer risk. Included were 216 postmenopausal Caucasian women with incident breast cancer and 282 community controls. DNA analyses suggested no increased breast cancer risk with the null GSTM1 genotype [odds ratio (OR) = 1.10; CI, 0.73-1.64], although there was some indication that the null genotype was associated with risk among the youngest postmenopausal women (OR = 2.44; CI, 0.89-6.64). Slightly elevated risk was associated with the CYP1A1 polymorphism (OR = 1.61; CI, 0.94-2.75) and was highest for those who smoked up to 29 pack-years (OR = 5.22; CI, 1.16-23.56). Statistical power to detect an effect may be limited by small numbers, and larger sample sizes would be required to corroborate these suggestive findings.
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PMID:Cytochrome P4501A1 and glutathione S-transferase (M1) genetic polymorphisms and postmenopausal breast cancer risk. 762 50

Tamoxifen is the major therapeutic agent for the treatment of hormone-dependent breast cancer. Tamoxifen treatment appears to be associated with an increased incidence of endometrial carcinoma in humans and hepatocellular carcinoma in rats. These carcinogenic effects of tamoxifen might be induced by the formation of a tamoxifen reactive intermediate that binds covalently to macromolecules. Liver microsomal cytochrome P450s (CYPs) catalyze the metabolism of tamoxifen, forming a reactive intermediate that binds irreversibly to microsomal proteins, primarily to a 54 kDa protein (Mani, C. and Kupfer, D., Cancer Res., 51, 6052-6058, 1991). The current study identifies the P450 enzymes that catalyze the activation of tamoxifen to a reactive intermediate in rats and humans. Among the species examined, rats, chickens and humans demonstrate low tamoxifen binding activity, ranging from 0.1 to 0.4 nmol bound/mg protein/h. In contrast, hamsters and mice exhibit high binding, 1.2 and 1.6 nmol/mg protein/h respectively. Treatment of male rats with phenobarbital or pregnenolone-16 alpha-carbonitrile (PCN) markedly elevated the binding of tamoxifen to liver microsomal proteins. Methylcholanthrene treatment had no effect on binding. These findings suggested the involvement of CYP3A in catalysis of the covalent binding. Alternate substrates of CYP3A, cortisol and erythromycin, inhibited tamoxifen binding in liver microsomes from PCN- and phenobarbital-treated rats. Treatment of rats with troleandomycin (TAO), an inducer of CYP3A, followed by the dissociation of the TAO-CYP3A complex, elevated the covalent binding to liver microsomes approximately 3-fold. Antibodies against rat CYP3A1 strongly inhibited tamoxifen binding to liver microsomes from PCN- and phenobarbital-treated rats, whereas the antibodies anti-CYP2B1/2B2 did not inhibit binding. In humans, tamoxifen binding was inhibited by the anti-rat CYP3A1 IgG and also by alternate substrates of CYP3A. These results indicate that the activation of tamoxifen to a reactive intermediate by rat and human liver microsomes is principally catalyzed by CYP3A enzymes.
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PMID:Involvement of cytochrome P4503A in catalysis of tamoxifen activation and covalent binding to rat and human liver microsomes. 800 Dec 26

Known breast-cancer risk factors account for only part of the variability in breast-cancer incidence. Tobacco smoke is not commonly considered a breast carcinogen, but many of its constituents, such as N-nitrosamines, are carcinogenic in laboratory animal studies. Herein, we assessed a cytochrome P4502E1 (CYP2E1) genetic polymorphism (a Dral restriction enzyme site in intron 6) as a risk factor for breast cancer in both premenopausal and postmenopausal women. Because N-nitrosamines are metabolically activated by CYP2E1, the risk among women smokers was investigated. Caucasian women were enrolled in a case-control study of breast cancer between 1986 and 1991. A subset of the women (219 premenopausal and 387 postmenopausal women) consented to phlebotomy. The allelic frequencies for the premenopausal women (D allele = 0.91 and C allele = 0.09) and postmenopausal women (D allele = 0.93 and C allele = 0.07) were similar to those previously reported. There was no statistically significant association between the CYP2E1 polymorphism and breast-cancer risk for premenopausal or postmenopausal women (adjusted odds ratio (OR) = 1.04, 95% confidence interval (CI) = 0.48, 2.24, and OR = 1.01, 95% CI = 0.55, 1.84, respectively). When the women were categorized as nonsmokers versus smokers (those who smoked more than one cigarette per week for more than 1 yr), premenopausal women with one or two C alleles who had a history of smoking were found to be at increased risk (unadjusted OR = 7.00, 95% CI = 0.75, 14.53, and adjusted OR = 11.09, 95% CI = 1.51, 81.41), although the number of study subjects with those genotypes was small. The small number of study subjects with a C allele precluded meaningful classification by level of smoking, but categorizing the smokers into two groups (above and below the median) also suggested an increased risk. Premenopausal women with the DD genotype and postmenopausal women with any genotype were not at increased risk. Breast-cancer risk was not related to the CYP2E1 genotype in either premenopausal nonsmokers or smokers (adjusted OR = 0.66, 95% CI = 0.20, 2.17, and OR = 2.13, 95% CI = 0.60, 7.59, respectively) or postmenopausal nonsmokers or smokers (OR = 0.90, 95% CI = 0.34, 2.35, and OR = 1.02, 95% CI = 0.46, 2.23, respectively), although the difference in the ORs for premenopausal nonsmokers and smokers suggests an increased risk for smokers. While there are limitations to this study, particularly related to the small number of subjects with the DC and CC genotypes, the study suggests that some women may be susceptible to tobacco smoke because of a CYP2E1 polymorphism. However, these results are preliminary and must be replicated.
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PMID:A cytochrome P4502E1 genetic polymorphism and tobacco smoking in breast cancer. 894 74

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