A new study has reported a mechanism of action by which alcohol (ethanol) acts as a human breast carcinogen. Acetaldehyde is the primary metabolite of alcohol, in other words, the compound that remains after alcohol is broken down (metabolized) by the body. The authors previously reported that exposure of human cells in the laboratory to acetaldehyde results in the activation of the Fanconi anemia-breast cancer susceptibility (FA-BRCA) DNA damage response network. Genomic DNA must be replicated during cell division, but damage to DNA interferes with replication. The FA-BRCA network is a set of proteins that react to DNA damage by coordinating DNA repair or assisting the replication machinery in bypassing the DNA damage, thereby enabling replication to proceed. The FA-BRCA network appears to be especially important in protecting against breast cancer.
To conduct the study, the authors first engineered HeLa cells (a cancer cell line derived from cervical cancer) to metabolize alcohol by expression of human alcohol dehydrogenase (ADH1B). In other words, the cells were engineered to metabolize alcohol into acetaldehyde by the same enzyme (ADH1B) that is expressed in human liver and breast tissue. The authors then determined whether generation of acetaldehyde from ethanol metabolism inside the cells could cause DNA damage and activate the FA-BRCA network.
In fact, incubation of HeLa-ADH1B cells with ethanol resulted in acetaldehyde production, which was shown to be prevented by co-incubation with a specific inhibitor of ADH. The ethanol incubation resulted in a four-fold increase in the acetaldehyde-DNA adduct and also triggered the activation of the FA-BRCA DNA damage response network in the cells. DNA adducts form when DNA bonds to a chemical mutagen. The binding of reactive carcinogens to DNA is considered the initiating event in chemical carcinogenesis. Importantly, the ethanol concentration used by the authors is within the range that can be reached in the human body during social drinking. The authors conclude that intracellular metabolism of ethanol to acetaldehyde results in DNA damage, which activates the FA-BRCA DNA damage response network. In a separate interiew, study author Phillip J. Brooks cautioned that "as our work was done in a cell culture system, using alcohol concentrations designed to correspond to blood alcohol levels attained during social drinking, it remains to be shown whether our findings reflect what happens in human body during alcohol drinking."