RGD Reference Report - The role of cytochromes p450 and aldo-keto reductases in prognosis of breast carcinoma patients. - Rat Genome Database

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The role of cytochromes p450 and aldo-keto reductases in prognosis of breast carcinoma patients.

Authors: Hlaváč, Viktor  Brynychová, Veronika  Václavíková, Radka  Ehrlichová, Marie  Vrána, David  Pecha, Václav  Trnková, Markéta  Kodet, Roman  Mrhalová, Marcela  Kubáčková, Kateřina  Gatěk, Jiří  Vážan, Petr  Souček, Pavel 
Citation: Hlaváč V, etal., Medicine (Baltimore). 2014 Dec;93(28):e255. doi: 10.1097/MD.0000000000000255.
RGD ID: 27226689
Pubmed: PMID:25526449   (View Abstract at PubMed)
PMCID: PMC4603110   (View Article at PubMed Central)
DOI: DOI:10.1097/MD.0000000000000255   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
AKR1A1Humanbreast cancer  IEP mRNA:increased expression:breastRGD 
Akr1a1Ratbreast cancer  ISOAKR1A1 (Homo sapiens)mRNA:increased expression:breastRGD 
Akr1a1Mousebreast cancer  ISOAKR1A1 (Homo sapiens)mRNA:increased expression:breastRGD 

Objects Annotated

Genes (Rattus norvegicus)
Akr1a1  (aldo-keto reductase family 1 member A1)

Genes (Mus musculus)
Akr1a1  (aldo-keto reductase family 1, member A1)

Genes (Homo sapiens)
AKR1A1  (aldo-keto reductase family 1 member A1)


Additional Information