The etiology of alcohol-induced breast cancer.

Breast cancer is the most common cancer in women in the United States, and it is second among cancer deaths in women. Results of most epidemiologic studies, as well as of most experimental studies in animals, have shown that alcohol intake is associated with increased breast cancer risk. Alcohol consumption may cause breast cancer through different mechanisms, including through mutagenesis by acetaldehyde, through perturbation of estrogen metabolism and response, and by inducing oxidative damage and/or by affecting folate and one-carbon metabolism pathways. Alcohol-metabolizing enzymes are present in human breast tissue. Acetaldehyde is a known, although weak, mutagen. However, results of some studies with human subjects implicate this agent in the context of genetic susceptibilities to increased ethanol metabolism. Reactive oxygen species, resulting from ethanol metabolism, may be involved in breast carcinogenesis by causing damage, as well as by generating DNA and protein adducts. Alcohol interferes with estrogen pathways in multiple ways, influencing hormone levels and effects on the estrogen receptors. With regard to one-carbon metabolism, alcohol can negatively affect folate levels, and the folate perturbation affects DNA methylation and DNA synthesis, which is important in carcinogenesis. Some study results indicate that genetic variants of one-carbon metabolism genes might increase alcohol-related breast cancer risk. For all these pathways, genetic polymorphisms might play a role in increasing further a woman's risk for breast cancer. Additional studies are needed to determine the relative importance of these pathways, as well as the modifying influence by genetic variation.