title: The role of cytochromes p450 and aldo-keto reductases in prognosis of breast carcinoma patients.
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.
authors.affiliation: From the Toxicogenomics Unit (VH, VB, RV, ME, DV, PS), National Institute of Public Health; 3rd Faculty of Medicine (VH, VB, ME), Charles University, Prague; Department of Oncology (DV), Palacky University Medical School and Teaching Hospital, Olomouc; Institute for the Care for Mother and Child (VP); Biolab Praha, Ltd (MT); Department of Pathology and Molecular Medicine (RK, MM); Department of Oncology (KK), University Hospital Motol, Prague; Department of Surgery (JG), Hospital Atlas; Tomas Bata University (JG); and Department of Pathology (PV), VELAB Ltd, Zlin, Czech Republic.
authors.forename: Viktor
authors.initials: V
authors.lastname: Hlaváč
authors.forename: Veronika
authors.initials: V
authors.lastname: Brynychová
authors.forename: Radka
authors.initials: R
authors.lastname: Václavíková
authors.forename: Marie
authors.initials: M
authors.lastname: Ehrlichová
authors.forename: David
authors.initials: D
authors.lastname: Vrána
authors.forename: Václav
authors.initials: V
authors.lastname: Pecha
authors.forename: Markéta
authors.initials: M
authors.lastname: Trnková
authors.forename: Roman
authors.initials: R
authors.lastname: Kodet
authors.forename: Marcela
authors.initials: M
authors.lastname: Mrhalová
authors.forename: Kateřina
authors.initials: K
authors.lastname: Kubáčková
authors.forename: Jiří
authors.initials: J
authors.lastname: Gatěk
authors.forename: Petr
authors.initials: P
authors.lastname: Vážan
authors.forename: Pavel
authors.initials: P
authors.lastname: Souček
mesh_terms: D000449:Aldehyde Reductase / Q000096:biosynthesis / Q000235:genetics*; D000074408:Aldo-Keto Reductases; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D011379:Prognosis; D011446:Prospective Studies; D012334:RNA, Neoplasm / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D012334:RNA, Neoplasm; D003577:Cytochrome P-450 Enzyme System; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase