Alcohol consumption and risk of breast cancer: An epidemiological investigaton of possible mechanisms
Platek, Mary E.
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Epidemiological and experimental animal evidence indicate that alcohol consumption is associated with an increase in breast cancer risk. While the attributable risk of alcohol in relation to breast cancer is modest, this association is of interest because exposure to alcohol is modifiable. Several mechanisms for this relationship have been hypothesized including altered one carbon metabolism and oxidative stress. Using a population based case control study, these two mechanisms were investigated in relation to breast cancer risk, examining genetic variation of key enzymes in the one carbon metabolism pathway, and mitochondrial DNA (mtDNA) mutation status of breast cancer tumors, as an indicator of oxidative stress. The data used in these investigations were collected as part of the Western New York Exposures and Breast Cancer Study, a case control study of women in Erie and Niagara Counties conducted from 1996 to 2001. To investigate the hypothesis that alcohol increases risk for breast cancer via alterations of the one carbon metabolism pathway, genotype for two separate genes critical in the pathway: MTHFR C677T, MTHFR A1298C and MTR A2756G were examined. We found no evidence for a main effect of the genetic polymorphisms on breast cancer risk, similar to previous results in the literature. However, we found increased risk of postmenopausal breast cancer among women with the MTHFR 677 TT genotype who were consuming high levels of alcohol throughout the lifetime compared to women with the MTHFR 677 CC genotype who were nondrinkers throughout the lifetime. This supports the hypothesis that alterations in the one carbon metabolism pathway, dependent on alcohol consumption, may affect breast cancer risk. Due to previous epidemiologic evidence that there may be an interaction between the polymorphic forms of MTHFR and MTR, this was investigated. The significance of having one or more than one variant in comparison to having the common alleles for either polymorphism of the MTR A2756G or the MTHFR C677T or the MTHFR A1298C was examined. Although the sample size was small, the direction of the odds ratios suggested that the number of variants one has may be important. We investigated the hypothesis that alcohol increases risk for breast cancer via an increase of mtDNA mutations. Mutation status was investigated in tumor blocks of breast cancer cases. Examination of mtDNA mutations as a proxy for oxidative stress in breast tumors is a novel approach and the investigation undertaken here was exploratory in nature. It was hypothesized that alcohol consumption would be related to mtDNA mutations; cases were selected for the assay based on drinking status. We found that somatic mtDNA mutations in breast tumors are frequent (47%) and that most mutations are in the D loop region. We did not find an increased likelihood of mutation with alcohol consumption. We did find some indication that among drinkers, MnSOD genotype was associated with risk, with lower risks among those with the TT genotype. It was also found that mtDNA mutations were more common in women without a family history of breast cancer and among women who do not use HRT. This suggested that the pathway resulting in breast cancer among women with a family history or among postmenopausal women who used HRT may not include mutations of the mtDNA. Additionally, this was the second report relating mtDNA mutations with ER negative tumors. It is unclear as to how alcohol consumption leads to breast cancer in some pre and postmenopausal women. It is likely that more than one mechanism is at play in the development of this multi factorial disease, and this is supported by the results reported here. Investigations of one carbon metabolism and oxidative stress in this population based case control study suggested that these two mechanisms play a role in the development of alcohol related breast cancer. Since it is possible to change breast cancer risk through changes in public health recommendations relating to alcohol intake, it is evident that we need further epidemiological studies that investigate potential underlying mechanisms for alcohol's association with breast cancer risk.