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The role of cytochromes P450 and aldo-keto reductases in prognosis of breast carcinoma patients

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dc.title The role of cytochromes P450 and aldo-keto reductases in prognosis of breast carcinoma patients en
dc.contributor.author Hlaváč, Viktor
dc.contributor.author Brynychová, Veronika
dc.contributor.author Václavíková, Radka
dc.contributor.author Ehrlichová, Marie
dc.contributor.author Vrána, David
dc.contributor.author Pecha, Václav
dc.contributor.author Trnková, Markéta
dc.contributor.author Kodet, Roman
dc.contributor.author Mrhalová, Marcela
dc.contributor.author Kubáčková, Kateřina
dc.contributor.author Gatěk, Jiří
dc.contributor.author Vážan, Petr
dc.contributor.author Souček, Pavel
dc.relation.ispartof Medicine (United States)
dc.identifier.issn 0025-7974 Scopus Sources, Sherpa/RoMEO, JCR
dc.identifier.issn 1536-5964 Scopus Sources, Sherpa/RoMEO, JCR
dc.date.issued 2014
utb.relation.volume 93
utb.relation.issue 28
dc.citation.spage e255
dc.type article
dc.language.iso en
dc.publisher Lippincott Williams and Wilkins
dc.identifier.doi 10.1097/MD.0000000000000255
dc.relation.uri http://journals.lww.com/md-journal/Fulltext/2014/12030/The_Role_of_Cytochromes_P450_and_Aldo_Keto.19.aspx
dc.description.abstract Metabolism of anticancer drugs affects their antitumor effects. This study has investigated the associations of gene expression of enzymes metabolizing anticancer drugs with therapy response and survival of breast carcinoma patients.Gene expression of 13 aldo-keto reductases (AKRs), carbonyl reductase 1, and 10 cytochromes P450 (CYPs) was assessed using quantitative real-time polymerase chain reaction in tumors and paired adjacent nonneoplastic tissues from 68 posttreatment breast carcinoma patients. Eleven candidate genes were then evaluated in an independent series of 50 pretreatment patients. Protein expression of the most significant genes was confirmed by immunoblotting.AKR1A1 was significantly overexpressed and AKR1C1-4, KCNAB1, CYP2C19, CYP3A4, and CYP3A5 downregulated in tumors compared with control nonneoplastic tissues after correction for multiple testing. Significant association of CYP2B6 transcript levels in tumors with expression of hormonal receptors was found in the posttreatment set and replicated in the pretreatment set of patients. Significantly higher intratumoral levels of AKR1C1, AKR1C2, or CYP2W1 were found in responders to neoadjuvant chemotherapy compared with nonresponders. Patients with high AKR7A3 or CYP2B6 levels in the pretreatment set had significantly longer disease-free survival than patients with low levels. Protein products of AKR1C1, AKR1C2, AKR7A3, CYP3A4, and carbonyl reductase (CBR1) were found in tumors and those of AKR1C1, AKR7A3, and CBR1 correlated with their transcript levels. Small interfering RNA-directed knockdown of AKR1C2 or vector-mediated upregulation of CYP3A4 in MDA-MB-231 model cell line had no effect on cell proliferation after paclitaxel treatment in vitro.Prognostic and predictive roles of drug-metabolizing enzymes strikingly differ between posttreatment and pretreatment breast carcinoma patients. Mechanisms of action of AKR1C2, AKR7A3, CYP2B6, CYP3A4, and CBR1 should continue to be further followed in breast carcinoma patients and models. en
utb.faculty Faculty of Humanities
dc.identifier.uri http://hdl.handle.net/10563/1004108
utb.identifier.obdid 43872693
utb.identifier.scopus 2-s2.0-84920114444
utb.identifier.wok 000346762200020
utb.identifier.coden MEDIA
utb.source j-scopus
dc.date.accessioned 2015-01-29T11:35:02Z
dc.date.available 2015-01-29T11:35:02Z
dc.description.sponsorship 13-25222J, GACR, Czech Science Foundation
dc.description.sponsorship Czech Science Foundation [13-25222J]; Internal Grant Agency of the Czech Ministry of Health [NT/14055-3]
dc.rights Attribution-NonCommercial-NoDerivs 4.0 Unported
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.access openAccess
utb.contributor.internalauthor Gatěk, Jiří
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