A potential inexpensive, widely-applicable approach to breast cancer prevention

Exposure to estrogens is a recognized risk factor for developing breast cancer. A variety of evidence from studies of estrogen metabolism, mutagenicity, cell transformation and carcinogenicity led to and supports the hypothesis that specific metabolites of estrogens initiate the series of events leading to breast cancer by reacting with DNA to form depurinating estrogen-DNA adducts. The resulting apurinic sites in DNA generate mutations in critical genes that can initiate breast and other human cancers. In fact, women with high risk for breast cancer (Gail Model score >1.66%) and women diagnosed with the disease have relatively higher levels of the depurinating estrogen-DNA adducts than do women at normal risk for breast cancer (p<0.001). This paradigm for the initiation of breast cancer suggests an approach to preventing breast cancer by use of specific antioxidant dietary supplements to prevent formation of the estrogen-DNA adducts, which would reduce the risk of initiating breast cancer. The antioxidants resveratrol and N-acetylcysteine efficiently reduce formation of estrogen-DNA adducts in cultured human breast epithelial cells. In addition, they prevent the transformation of these cells into malignant cells that induce tumors in severely compromised immunodeficient mice. These results demonstrate that the two antioxidants show promise as cancer-preventing agents. We have also demonstrated that N-acetylcysteine reduced the formation of estrogen-DNA adducts in a pilot study of human subjects. These two compounds need to be evaluated as potential inexpensive, widely-applicable agents to prevent human breast and other types of cancer. Their use in human populations will be discussed.