ABSTRACT
BACKGROUND: The expression pattern of cytochrome P450 genes (CYPs) affected by tumorigenesis may have an important role in the progression of cancer and in the metabolism of anticancer drugs. The aim of the study was to determine the expression patterns of four cytochrome P450 genes (CYP1B1, 2C9, 2E1 and 3A4) in breast cancer patients. PATIENTS AND METHODS: mRNA expression was quantified by real-time PCR. Analyses of 40 sets of human breast tumors, adjacent non-tumor tissues and of 18 peripheral blood lymphocyte samples were performed. Expression levels were tested for correlation with clinical and pathological data of patients. RESULTS: Expression levels of CYP2C9 and CYP3A4 were negligible. CYP1B1 expression was on average 50-fold higher than that of CYP2E1 with overexpression detected in one third of the tumors. Correlation of CYP1B1 expression in lymphocytes with that in non-tumor tissues was found. Significantly higher CYP2E1 expression was associated with an invasive lobular type of tumor, locally advanced disease as well as with non-tumor tissue of progesterone receptor-negative patients. CONCLUSION: CYP2E1 expression has a potential role as a breast cancer prognosis marker. The observed high CYP1B1 expression in tumor cells may evoke changes in their response to drugs which are substrates of P450 1B1 and influence metabolism or activation of environmental carcinogens.
Subject(s)
Biomarkers, Tumor/analysis , Breast Neoplasms/enzymology , Cytochrome P-450 Enzyme System/biosynthesis , RNA, Messenger/analysis , Adult , Breast Neoplasms/genetics , Cytochrome P-450 Enzyme System/genetics , Female , Gene Expression , Humans , Immunohistochemistry , Middle Aged , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
We aimed at determining whether any association exists between genetic polymorphisms in epoxide hydrolase (EPHX1), NADPH-quinone oxidoreductase (NQO1), glutathione S-transferases (GSTM1/P1/T1) and individual susceptibility to breast cancer. Polymerase chain reaction-restriction fragment length polymorphism-based genotyping assays were used to determine the frequency of polymorphisms in EPHX1 (exons 3 and 4), NQO1 (exon 6), GSTM1 (deletion), GSTP1 (exon 5), and GSTT1 (deletion) in a case-control study comprised of 238 patients with breast cancer and 313 healthy individuals. The distribution of genotypes in exon 6 of NQO1 was significantly different between the control group and breast cancer cases. Age-adjusted odds ratio (OR) for variant genotype NQO1*2/*2 was 3.68 (confidence interval (CI) = 1.41-9.62, P = 0.008). Association of GSTP1*2/*2 genotype as well as that of low EPHX1 activity deduced by combinations of genotypes in exons 3 and 4 with breast cancer was suggestive, but nonsignificant. Individuals simultaneously lacking GSTM1 and carrying at least one GSTP1 variant allele were at significantly higher risk of breast cancer (OR = 2.03, CI = 1.18-3.50, P = 0.010). Combinations of either GSTM1null or GSTP1*2 with low activity of EPHX1 presented significant risk of breast cancer (OR = 1.88, CI = 1.00-3.52, P = 0.049 and OR = 2.40, CI = 1.15-5.00, P = 0.019, respectively) as well. In conclusion, the results suggest that genetic polymorphisms in biotransformation enzymes may play a significant role in the development of breast cancer.
