Abstract
BackgroundSince targeting oxidative stress markers has been recently recognized as a novel therapeutic target in cancer, it is interesting to investigate whether genetic susceptibility may modify oxidative stress response in cancer. The aim of this study was to elucidate whether genetic polymorphism in the antioxidant enzymes is associated with lipid peroxidation in breast cancer.MethodsWe conducted a study among Polish women, including 136 breast cancer cases and 183 healthy controls. The analysis included genetic polymorphisms in five redox related genes: GPX1 (rs1050450), GPX4 (rs713041), SOD2 (rs4880), SEPP1 (rs3877899) and SEP15 (rs5859), lipid peroxidation, the activities of antioxidant enzymes determined in blood compartments as well as plasma concentration of selenium – an antioxidant trace element involved in cancer. Genotyping was performed using the Real Time PCR. Lipid peroxidation was expressed as plasma concentration of thiobarbituric acid reactive substances (TBARS) and measured with the spectrofluorometric method. Glutathione peroxidase activity was spectrophotometrically determined in erythrocytes (GPx1) and plasma (GPx3) by the use of Paglia and Valentine method. Spectrophotometric methods were employed to measure activity of cytosolic superoxide dismutase (SOD1) in erythrocytes (Beauchamp and Fridovich method) and ceruloplasmin (Cp) in plasma (Sunderman and Nomoto method). Plasma selenium concentration was determined using graphite furnace atomic absorption spectrophotometry.ResultsBreast cancer risk was significantly associated with GPX1 rs1050450 (Pro198Leu) polymorphism, showing a protective effect of variant (Leu) allele. As compared to the control subjects, lipid peroxidation and GPx1 activity were significantly higher in the breast cancer cases, whereas ceruloplasmin activity was decreased. After genotype stratification, both GPx1 activity and TBARS concentration were the highest in GPX1 Pro/Pro homozygotes affected by breast cancer. At the same time, there was a significant correlation between the level of lipid peroxidation and GPx1 activity among the cancer subjects possessing GPX1 Pro/Pro genotype (r = 0.3043; p = 0.0089), whereas such a correlation was completely absent in the cases carrying at least one GPX1 Leu allele as well as in the controls (regardless of GPX1 genotype).ConclusionsGPX1 polymorphism may be an important factor modifying oxidative stress response in breast cancer subjects. Further studies are needed to elucidate its potential clinical significance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1680-4) contains supplementary material, which is available to authorized users.
Highlights
Since targeting oxidative stress markers has been recently recognized as a novel therapeutic target in cancer, it is interesting to investigate whether genetic susceptibility may modify oxidative stress response in cancer
Significant differences in allele frequencies were noted for the Cytosolic glutathione peroxidase (GPX1) rs1050450 polymorphism, for which carrying at least one variant allele (GPX1 Leu) was associated with a decreased risk of cancer both, in the univariate analysis and after adjustment for age, Body mass index (BMI), smoking status and menopausal status (Table 2)
The analysis of relevant gene-gene interactions was conducted for GPX1 x Mitochondrial superoxide dismutase (SOD2) and GPX1 x Selenoprotein P (SEPP1) and did not reveal any significance
Summary
Since targeting oxidative stress markers has been recently recognized as a novel therapeutic target in cancer, it is interesting to investigate whether genetic susceptibility may modify oxidative stress response in cancer. Targeting oxidative stress markers has been recently recognized as a novel therapeutic approach in cancer treatment, due to the fact that generation of reactive oxygen species (ROS) as well as some products of lipid peroxidation may improve effectiveness of the treatment by decreasing cancer progression and reducing drug resistance. Mechanisms underlying these effects (and reviewed recently by Barrera [3]) are mainly associated with the induction of apoptosis in cancer cells by overcoming their antioxidant defense. Targeting ROS has been suggested as a potential determinant of effective treatment in cancer [4, 5]
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