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)

P450 aromatase catalyzes the conversion of androgens to estrogens and plays a key role in the cell growth of hormone-dependent breast cancer in postmenopausal women. On the other hand, matrix metalloproteinases (MMPs), which can degrade almost all components of the extracellular matrix, play a crucial role in tumor cell invasion and cancer metastasis. In the present study the effect of letrozole on cell proliferation of estrogen receptor (ER)-positive MCF-7 human epithelial breast cancer and MCF-12A human mammary epithelial cells was studied. The effect of letrozole on the in vitro release of MMPs, particularly type IV collagenases (MMP-2 and MMP-9), by the ER-positive MCF-7 cells was also investigated, using a solid-phase method of high sensitivity and accuracy. Using RNA isolates from cell lines MCF-7 and MCF-12A, reverse transcriptase-polymerase chain reaction analysis revealed that only MCF-7 cells express the P450 aromatase gene. Study of the effects of letrozole alone and the hormones 17-beta-estradiol, testosterone and 4-androstene-3, 17-dione in the presence and absence of letrozole on cell growth at the DNA synthesis level showed that letrozole significantly suppressed the endogenous aromatase-induced proliferation of MCF-7 cells. The majority of MMPs secreted by MCF-7 cells were identified in their pro-forms, which was in accordance with the low metastatic potential determined for these cells. After treatment of cells with letrozole (10 nM) for 24 and 48 h, significant inhibition of MMP levels was obtained. Furthermore, concurrent treatment of MCF-7 cells with 17-beta-estradiol in the presence of letrozole significantly suppressed the estradiol-induced stimulation of MMP levels. The data obtained suggest that letrozole is a potent in vitro inhibitor of cell proliferation and of type IV collagenases expressed by ER-positive MCF-7 cells and may be of value for suppressing breast tumor growth and invasiveness.
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PMID:Letrozole as a potent inhibitor of cell proliferation and expression of metalloproteinases (MMP-2 and MMP-9) by human epithelial breast cancer cells. 1256 69

Aromatase (P450 arom) is a target of pharmacological interest for the treatment of breast cancer. New series of 7-(alpha-azolylbenzyl)-1H-indoles and indolines were synthesized as non-steroidal inhibitors of P450 arom. Selectivity was studied towards P450 17alpha enzyme. The most active compound, 1-ethyl-7-[(imidazol-1-yl)(4-chlorophenyl)methyl]-1H-indole 12c exhibited promising relative potency (rp) of 336 (rp of aminoglutethimide=1) and most of the described azoles were active and selective towards P450 arom.
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PMID:Preparation and pharmacological profile of 7-(alpha-azolylbenzyl)-1H-indoles and indolines as new aromatase inhibitors. 1269 53

Tirapazamine (TPZ) is the lead member of a class of bioreductive drugs currently in phase II and III clinical trials. TPZ requires metabolic activation to give a cytotoxic free radical species, and this hypoxia-mediated process is carried out by a variety of cellular reductases, including NADPH cytochrome c (P450) reductase (P540R). Nitric-oxide synthase (NOS) is widely expressed in human tumors, and this enzyme consists of an oxidase and a reductase domain, the latter showing striking homology to P450R. Thus, in this article, we have investigated the role of one of the cytosolic isoforms of NOS [inducible NOS (NOSII)] in the bioactivation of this DNA-damaging antitumor agent. To achieve this, we have constitutively overexpressed NOSII in human breast tumor MDA231 cells by employing an optimized expression vector in which the strong human polypeptide chain elongation factor 1alpha promoter drives a bicistronic message encoding the genes for human NOSII and the puromycin-resistant gene (pac). Subcellular localization of NOSII in the stably transfected clones was determined after differential centrifugation and showed that NOSII catalytic activity was exclusively cytosolic as determined by conventional activity assay. This was confirmed by immunostaining followed by fluorescent microscopy studies. The increase in NOSII activity in a series of transfected clones was associated with an increase in TPZ metabolism and toxicity under hypoxic conditions. There was no similar increase in aerobic toxicity. These findings are of significance for two reasons. First, cellular NOSII activity, similar to that seen in human breast cancer, could contribute to TPZ toxicity; second, this will be a result of NOS-derived/cytosol-associated TPZ radicals.
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PMID:Non-nuclear localized human NOSII enhances the bioactivation and toxicity of tirapazamine (SR4233) in vitro. 1276 34

An increased risk of developing endometrial cancer is observed in breast cancer patients treated with tamoxifen (TAM) and in healthy women undergoing TAM chemoprevention therapy. TAM-DNA adducts were detected in the endometrium of women taking TAM (Shibutani, S., et al. (2000) Carcinogenesis 21, 1461-1467) and are formed primarily through O-sulfonation of alpha-hydroxytamoxifen (alpha-OHTAM). To explore the genotoxicic mechanisms of TAM, TAM was incubated with one of multiple human cytochrome P450 enzymes, i.e., P450 1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, 3A7, 4A11, 4F2, 4F3A, or 4F3B, in a NADPH regenerating system, and the metabolites were identified using HPLC/UV analysis with authentic standards. Among the 18 human P450 enzymes, P450 3A4 generated a significant amount of alpha-OHTAM. When some rat P450 enzymes were examined, P450 3A2 also catalyzed alpha-hydroxylation of TAM. Similarly, human P450 3A4 and rat P450 3A1 and 3A2 converted toremifene (TOR, a chlorinated TAM analogue) to alpha-hydroxytoremifene (alpha-OHTOR). The formation of alpha-OHTAM and alpha-OHTOR by these P450 enzymes was confirmed by tandem mass spectroscopy. Only the P450 3A subfamily enzymes are able to alpha-hydroxylate TAM and TOR. Although the formation of alpha-OHTOR by these enzymes was much higher than that of alpha-OHTAM, TOR is known to be much less genotoxic than TAM. The results support our proposed mechanism that the lower genotoxicity of TOR is due to limited O-sulfonation of alpha-OHTOR by hydroxysteroid sulfotransferases, resulting in the poor formation of DNA adducts (Shibutani, S., et al. (2001) Cancer Res. 61, 3925-3931).
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PMID:Alpha-hydroxylation of tamoxifen and toremifene by human and rat cytochrome P450 3A subfamily enzymes. 1297 2

The aryl hydrocarbon receptor (AhR), when activated by exogenous ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), regulates expression of several phase I and phase II enzymes and is also involved in the regulation of cell proliferation. Several studies suggest that endogenous AhR ligand(s) may exist. One putative endogenous ligand is indirubin, which was recently identified in human urine and bovine serum. We determined the effect of indirubin in MCF-7 breast cancer cells on induction of the activities of cytochromes P450 (CYP) 1A1 and 1B1, as measured by estradiol and ethoxyresorufin metabolism, and on induction of the CYP1A1 and CYP1B1 mRNAs. With 4-hr exposure, the effects of indirubin and TCDD at 10nM on CYP activity were comparable, but the effects of indirubin, unlike those of TCDD, were transitory. Indirubin-induced ethoxyresorufin-O-deethylase activity was maximal by 6-9 hr post-exposure and had disappeared by 24 hr, whereas TCDD-induced activities remained elevated for at least 72 hr. The effects of indirubin on CYP mRNA induction were maximal at 3 hr. Indirubin was metabolized by microsomes containing cDNA-expressed human CYP1A1 or CYP1B1. The potency of indirubin was comparable to that of TCDD in a CYP1B1-promoter-driven luciferase assay, when MCF-7 cells were co-exposed to the AhR ligands together with the CYP inhibitor, ellipticine. Thus, if indirubin is an endogenous AhR ligand, then AhR-mediated signaling by indirubin is likely to be transient and tightly controlled by the ability of indirubin to induce CYP1A1 and CYP1B1, and hence its own metabolism.
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PMID:Transient induction of cytochromes P450 1A1 and 1B1 in MCF-7 human breast cancer cells by indirubin. 1463 89

The P450 family of proteins has more than 1000 representatives, which despite sometimes relatively low sequence identity have a surprisingly high level of structural similarity. This fact makes this family of proteins ideal candidate for various types of modeling based on protein structure prediction. A number of P450 proteins, including CYPs 1A1, 1A2, 1B1, 3A4, 11B2, 17, and 19, play a role in the metabolism of estrogen. Inhibitors of these proteins could be very promising drugs for hormonal treatment of postmenopausal breast cancer. Population studies have yielded a significant amount of data describing the relationship between single nucleotide polymorphisms (SNP) in DNA and cancer risk related to these proteins. A combination of SNP analysis with protein structure prediction can be a very useful strategy in investigations of structure-functional relations of P450 proteins and structure-based drug design. Here we will demonstrate how protein structure prediction combined with genetic SNP analysis can be useful for potential drug design and possibly, individual treatment of breast cancer.
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PMID:SNP analysis combined with protein structure prediction defines structure-functional relationships in cancer related cytochrome P450 estrogen metabolism. 1503 1

The diaziridiny/benzoquinone RH1 is shortly to enter a phase I clinical trial. The drug was originally designed as a substrate for the enzyme DT-diaphorase (DTD) such that metabolic activation of the drug would lead to toxicity. To evaluate this, we have measured the toxicity of RH1 in a pair of non-small cell lung cancer (NSCLC) cell lines of widely differing levels of DTD and in MDA231 breast cancer cells which have been engineered to overexpress DTD. In addition, we have explored the importance of the putative one-electron reductase, P450 reductase, by assessing the toxicity of RH1 in MDA231 cells engineered to overexpress the enzyme. All drug exposures were carried out under hypoxic and aerobic conditions. Those cells with the highest levels of DTD, i.e. D7 versus MDA231 wt and H460 versus H596, are substantially more sensitive to RH1 than the cell lines expressing low DTD activity. Those cells with the lowest levels of DTD activity, i.e. MDA231 wt, R4 and H596, show much greater sensitivity to RH1 under hypoxic conditions compared to aerobic conditions. Finally, overexpression of P450 reductase, i.e. comparing MDA231 wt with R4, has little, if any, impact on the toxicity of RH1 under hypoxic or aerobic conditions. In summary, RH1 can be effective in killing cells containing high levels of DTD and may be useful in treating tumors expressing this enzyme.
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PMID:The importance of DT-diaphorase and hypoxia in the cytotoxicity of RH1 in human breast and non-small cell lung cancer cell lines. 1509 Jul 46

The production of estrogen from androgen via the estrogen biosynthesis pathway is catalyzed by aromatase P450 (CYP19). To assess the association between breast cancer risk and a polymorphism at codon 39 Trp/Arg of the encoding gene, a case-control study was conducted at Aichi Cancer Center Hospital in Japan. Subjects were 248 histologically confirmed breast cancer patients and 603 hospital controls without cancer. Odds ratios (OR) and 95% confidence intervals (95% CI) were determined by logistic regression analysis. The allele frequency among controls was 3.8% for the C allele, and the OR (95% CI) of the polymorphism relative to TT genotype was 1.21 (0.69-2.14) for TC/CC genotypes combined. There was no association between CYP19 gene polymorphism and breast cancer risk in the study group as a whole, but homozygous and heterozygous carriers of the variant Arg allele showed a significantly increased risk of breast cancer among premenopausal women with a late age at first full-term pregnancy (OR 7.31, 95% CI 1.88-28.5) or a high body mass index (OR 2.77, 95% CI 1.12-6.87). Additional larger studies should be done to confirm that the rare CYP19 variant increases the risk of breast cancer among premenopausal Japanese women.
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PMID:The CYP19 gene codon 39 Trp/Arg polymorphism increases breast cancer risk in subsets of premenopausal Japanese. 1529 66

The position of the nitro group determines the relative carcinogenic activities of mono-nitropyrene isomers (mono-NPs) in the rat mammary gland. To determine whether the results obtained in rodents treated with these environmental pollutants can be applicable to humans, we examined their metabolic activation in primary cultures of human breast cells derived from reduction mammoplasty, as well as in the cultured human breast cancer cell line MCF-7 and the immortalized human mammary epithelial cell line MCF-10A. Primary cultures as well as cell lines were competent in metabolizing all three isomers via both ring oxidation and nitro reduction pathways. Qualitatively similar metabolic patterns were observed but quantitative differences were evident. On the basis of cochromatography with synthetic standards in two HPLC systems, metabolites of 1-NP were identified as 1-OH-Py, 3-, 6-, and 8-OH-1-NP and 1-AP. In the case of 2-NP, 6-OH-2-NP and 2-AP were identified. 4-NP was metabolized to 9,10-DHD-4-NP, Py-4,5-Q, 9,10-Q-4-NP, 9/10-OH-4-NP, 6/ 8-OH-4-NP, and 4-AP. Varying degrees of sulfate and glucuronide conjugation of mono-NP metabolites were detected. In MCF-7 cells, we found that 1-, 2-, and 4-NP bind to DNA at levels of 68, 17, and 132 pmol/mg DNA, respectively. Following HPLC analysis of the DNA hydrolysates, we detected multiple DNA adducts including those derived from nitro reduction of 2- and 4-NP; however, none was detected in the case of 1-NP. To determine the P450 enzymes responsible for the metabolic activation of these carcinogens, we incubated [(3)H]mono-NPs with recombinant human P450 1A1 or 1B1. Metabolites identified were primarily derived from ring oxidation; both P450s 1A1 and 1B1 yielded similar metabolic profiles. This is the first report demonstrating that human breast (target organ) cells, immortalized human mammary epithelial cell line MCF-10A, and breast cancer cell line MCF-7 are capable of activating mono-NPs to metabolites that can damage DNA.
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PMID:Human cytochromes P450 1A1 and 1B1 catalyze ring oxidation but not nitroreduction of environmental pollutant mononitropyrene isomers in primary cultures of human breast cells and cultured MCF-10A and MCF-7 cell lines. 1531 Feb 39

This study investigated the ability of amitraz, a formamidine insecticide, to induce cytochrome P450-dependent monooxygenases and to disrupt estrogenic activity in human breast cancer MCF-7 cells and immature female rats. In MCF-7 cells, treatment with 10 microM amitraz for 24 h increased 7-ethoxyresorufin O-deethylase activity in cell homogenate. Treatment of MCF-7 cells with 1 and 10 microM amitraz for 3 h replaced previously bound [(3)H]17beta-estradiol (E(2)) from estrogen receptors. Treatment with 0.1 and 1 microM amitraz for 2 days inhibited [(3)H]thymidine incorporation into the DNA of MCF-7 cells while the inhibition was blocked in cells co-treated with 1 nM E(2) and amitraz. In immature female rats, treatment with 50 mg/kg amitraz intraperitoneally for 3 days increased cytochrome P450 content, 7-ethoxyresorufin, methoxyresorufin and pentoxyresorufin O-dealkylases, and benzo[a]pyrene hydroxylase activities in liver microsomes. The results of immunoblot analysis revealed that amitraz induced liver microsomal CYP1A1/2, 2B1/2B2, and 3A proteins. Treatment with 10 and 25 mg/kg amitraz for 3 days dose-dependently decreased uterine weight and peroxidase activity in immature female rats while the decreases were blocked in rats co-treated with 10 microg/kg E(2) and 10 or 25 mg/kg amitraz. These in vitro and in vivo findings suggest that amitraz induces multiple forms of P450 and exerts weak antiestrogenic activity.
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PMID:Effects of amitraz on cytochrome P450-dependent monooxygenases and estrogenic activity in MCF-7 human breast cancer cells and immature female rats. 1535 Jun 76


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