Abstract
4497
The proximate cause of cancer cell death by radiation therapy and numerous chemotherapeutic agents is through generation of reactive oxygen species (ROS), causing lipid peroxidation, additional ROS, and oxidative stress. Oxidative stress not only results in damage to DNA and proteins, but also causes membrane disruption that can lead to mitochondrial damage, triggering the apoptotic cascade. MnSOD, present in mitochondria and hypothesized to be a tumor suppressor gene in human breast cancer, catalyzes conversion of superoxide radicals to H2O2. Myeloperoxidase, also present in breast tissue, converts H2O2 and Cl to HOCl, which has oxidizing properties. Variants in MnSOD and MPO have been identified that have functional effects on gene products, with the MnSOD T allele and MPO G allele putatively associated with higher H2O2 and HOCl levels, respectively. We hypothesized that variants in these genes could impact the efficacy of treatment for breast cancer, resulting in differential survival by genotype, and that the greatest effects might be observed among women with genotypes likely to result in higher levels of H2O2 and subsequent higher levels of ROS-generating HOCl. Women who were treated with radiation and/or chemotherapy for incident breast cancer at the Arkansas Cancer Research Center from 1985 to 1996 were identified through the Tumor Registry (n=271). DNA was extracted for genotyping from tissue from paraffin-embedded normal lymph nodes, and MnSOD and MPO genotypes were determined using mass spectrometry (MALDI-TOF, Bioserve Biotechnologies, Ltd.). Overall survival in relation to genotypes was evaluated using Kaplan-Meier survival function and Cox Proportional Hazards models, adjusted for age, race, stage, ER and PR status, and treatments received. Women who were homozygous for MnSOD T alleles had somewhat reduced hazard of death (HR(95%CI)= 0.79 (0.46-1.35) compared to women with CT and CC genotypes, although associations were not statistically significant. Similarly, women with MPO G alleles, associated with increased transcription, were also observed to have better survival (HR(95%CI)= 0.592 (0.368-0.950). When we combined genotypes for MnSOD and MPO, women who carried both MnSOD TT and MPO GG genotypes had more than a two-fold decrease in hazard of death compared to those with ’low-risk’ genotypes (HR (95% CI)=0.45 (0.23-0.90). These data indicate that gene variants that impact levels of ROS and oxidative stress may modify prognosis after treatment for breast cancer. Further studies with more homogeneous patient populations and standardized treatment regimens need to be conducted to confirm these findings. (Supported by grant from the Arkansas Breast Cancer Research Fund)
[Proc Amer Assoc Cancer Res, Volume 45, 2004]