We examined the role of alcohol intake, genes in the alcohol metabolism pathway and their interaction in the development of incident breast cancer in post-menopausal women. As has been observed in many previous observational studies [2
], women with incident breast cancer in this study had a significantly higher daily alcohol intake than controls, with increasing risk observed along with increasing average daily alcohol intake.
The genes responsible for alcohol metabolism were selected for this study because of the metabolic pathway for alcohol (). The polymorphisms in the alcohol metabolizing genes were selected because of previous studies in the medical literature. As mentioned previously, markers in the gene responsible for aldehyde dehydrogenase were not genotyped in this study because it is not polymorphic in Caucasians and therefore not relevant to this primarily Caucasian study population. It would be worth genotyping in Asian populations where the gene is found to be polymorphic.
Alcohol dehydrogenase oxidizes ethanol to acetaldehyde. The SNP selected in ADH1B (ADH2), rs1229984, is non-synonymous. It is a haplotype-tagging SNP on chromosome 4 that results in arginine to histidine change. The SNP selected in ADH1C (ADH3), rs698, is also a non-synonymous haplotype-tagging SNP on chromosome 4, resulting in isoleucine to valine change. We found differences in the magnitude and direction of the effect of alcohol intake on risk of breast cancer in the PLCO cohort by both ADH1B and ADH1C genotype, with the A allele of ADH1B appearing to be protective. A case-only study in primarily post-menopausal women in Germany demonstrated an interaction between ADH1B and alcohol intake in women with invasive breast cancer. [7
] A recent case-control study reported a potential protective association between ADH1B*896G and breast cancer in women with a mean age of 57 years, more than one-quarter of whom were pre-menopausal. [19
In women with invasive breast cancer, there was an inverse association between the ADH2 polymorphism and frequency of alcohol consumption in relation to risk of breast cancer. Similarly, we observed a protective affect for the A allele of ADH2. Three prior studies failed to find significant associations between alcohol intake and breast cancer risk in post-menopausal women when stratified by ADH3 genotype, although their data suggested an interaction which may not have been able to be detected due to lack of power. [8
Cytochrome P450 also oxidizes ethanol to acetaldehyde, although it is only induced by heavy drinking. The SNP selected for this study, rs2031920, located on chromosome 10, acts in the 5’ flanking region of the gene to decrease enzyme activity in drinkers. One prior study demonstrated an interaction between alcohol intake and CYP2E1 genotype and risk of breast cancer in alcohol-consuming Korean women, although their findings were not statistically significant due to small sample size for the minor allele. [10
] The findings were similar regardless of menopausal status. The magnitude of the effect of current alcohol intake on breast cancer risk in our study (OR ranging from 1.32 to 1.96) was slightly greater than was observed in the Korean study (OR=1.4), perhaps because of the importance of aldehyde dehydrogenase in the Korean population.
Higher levels of acetaldehyde due to alterations in the oxidative pathway because of genetic polymorphisms may explain the association between alcohol intake and risk of breast cancer. Another potential mechanism to explain this association is a modulating effect on estrogen metabolism or receptors. [22
] Interaction between alcohol intake and estrogen and progesterone (ER/PR) receptor status of the breast cancer tumor has been observed in previous studies [23
], as well as a synergistic effect of alcohol intake and estrogen replacement therapy [29
], further supporting the hypothesis that alcohol influences hormonal status to increase breast cancer risk. ER/PR status is not currently available for PLCO cohort.
The advantages of this study include the relatively large sample size, the fact that the information about alcohol intake was collected prior to breast cancer diagnosis, and the available information about other risk factors for breast cancer. Limitations include the relative lack of ethnic diversity in the study sample and the limited sample size to assess gene/gene interactions. Also, because acetaldehyde is known to play a major role in producing unpleasant symptoms after alcohol intake, such as facial flushing, palpitations, headache, vomiting and sweating [26
], women who are “poor metabolizers” may self-select into the non-drinking or lower levels of drinking groups, thus effectively decreasing the sample size of moderate or heavier alcohol drinkers and further decreasing the power to detect an association of moderate or heavy alcohol intake with breast cancer when stratified by genotype. There is some indication in the current data set that this self-selection does occur.
In conclusion, alcohol intake, genes involved in alcohol metabolism and the interaction of alcohol intake and alcohol metabolism genes increase the risk of breast cancer in post-Alcohol, genetics and breast cancer menopausal women. Further research to investigate these effects in other ethnic groups and a larger sample size to quantify gene/gene interactions are warranted. In addition, the inclusion of estrogen and progesterone receptor status would allow the investigation of potential interaction with tumor status.