Reactive oxygen species derive from a number of different sources, and traditional and putative breast cancer risk factors can be linked to the disease by an oxidative stress mechanism, for example: 1) steroid hormones, as well as some environmental organochlorines, are metabolized to reactive quinones and hydroquinones, which can directly damage DNA; 2) the metabolism of alcohol results in production of ROS and damage to DNA; 3) BRCA1 is needed for post-transcriptional repair of oxidative damage, indicating that oxidative stress may be an important risk factor for women with a family history of the disease; and 4) the inverse relationship noted with consumption of fruits and vegetables could be related to their being a source of antioxidant vitamins. Also, several markers of oxidative stress in a number of studies were higher in women with breast cancer and those at high risk than among non-diseased women. Endogenous factors affect not only the generation of ROS, but also an antioxidant response to them. We propose that inter-individual variability in genes that encode enzymes with pro-oxidant and antioxidant activities will have an impact on the generation of ROS and ultimately on breast cancer risk. Furthermore, we hypothesize that risk associated with metabolic variability will be associated with exposure to exogenous factors that increase the likelihood of production of ROS. In this project, we propose to evaluate this hypothesis utilizing data from the Long Island Breast Cancer Study Project. DNA isolated from the blood samples donated by a large population-based sample of breast cancer case and control women will be assayed for three different types of ROS-related genetic polymorphisms including: regulatory regions of enzymes or processes that generate ROS (myeloperoxidase and tumor necrosis factor-alpha); those that prevent oxidative stress by neutralizing ROS (extracellular and manganese superoxide dismutase, glutathione peroxidase, catalase and glutathione S-transferase Mi); and those that will affect ultimate levels of ROS generated by the metabolism of steroid hormones (catechol O-methyltransferase, glucuronosyltransferase). In addition to the large number of subjects for whom samples are available for the laboratory analyses (n = 1087 cases and 1122 controls), comprehensive assessment of the subjects? environmental exposures has already been obtained in the parent study. Thus, we can also explore whether the genetic polymorphisms in ?at-risk? genotypes will affect associations between breast cancer risk and factors that are likely to be related through an oxidative stress mechanism, such as fruit and vegetable intake, reproductive and hormonal factors, alcohol consumption, and environmental contaminants (organochlorines and PAHs). Results from this project can be confirmed utilizing data from the Carolina Breast Cancer Study.
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