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.
Subject(s)
Aldehyde Reductase/genetics , Breast Neoplasms/genetics , Cytochrome P-450 Enzyme System/genetics , Gene Expression Regulation, Neoplastic , RNA, Neoplasm/genetics , Aldehyde Reductase/biosynthesis , Aldo-Keto Reductases , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Proliferation , Cytochrome P-450 Enzyme System/biosynthesis , Female , Flow Cytometry , Humans , Immunoblotting , Prognosis , Prospective Studies , Real-Time Polymerase Chain Reaction , Tumor Cells, CulturedABSTRACT
INTRODUCTION: Breast conserving surgery combined with sentinel node biopsy represents currently the gold standard of treatment for early breast cancer. Although breast conserving surgery has been a widely accepted method for many years, there remain some highly controversial unresolved issues. The present analysis focused on the resection margin as one of the key factors for local control of the disease. METHODS: Patient disease free survival and overall survival were collected from patients undergoing breast conserving surgery from 2004 to 2009 at the Department of Surgery Atlas hospital Zlin, Czech Republic. All patients with resection margin less then 5 mm were re-resected to achieve this clear resection margin of 5mm or more. Disease free survival (more specifically local relapse free survival, metastasis free survival and regional free survival) and overall survival were assessed. RESULTS: The data on 330 patients were analyzed and 286/330 cases had complete follow-up. After a median follow-up of 70 months, 7 patients with isolated local relapse were identified (2.44%), 13 patients with distant metastasis without local relapse (4.54%) and 2 patients with relapse in the axilla without local relapse in the breast (0.7%). CONCLUSION: The final decision about the extent of resection margin remains controversial but based on the data on local control presented here it seems reasonable to increase the criteria for a clear resection margin to 5 mm.
