Epidemiological studies have identified an association of elevated levels of estrogens with breast cancer development. In particular, the natural hormone, 17b-estradiol (E2) and its hydroxylated metabolites, particularly, 4-hydroxyestradiol (4-E2), which are known animal carcinogens, have been implicated and it is proposed that these substances cause free radical-mediated DNA damage, a key step involved in the development of breast cancer. We have detected novel, polar DNA adducts in rat and human tissues, including mammary tissue, by a newly developed 32p-postlabeling/TLC assay. Chromatographic similarity with reference hydroxylated and cyclic adducts suggested that the endogenous DNA adducts presumably resulted from oxygen free radical-mediation. Adduct levels in rats were increased after treatment with E2 and 4-E2, further supporting the involvement of free radicals in the adduct formation. Cu2+-mediated activation of 4-E2 in the presence of DNA also resulted in polar adduct formation. Some of the adducts formed in vitro and in vivo were chromatographically similar. Taken together these results suggest that the polar adducts may result, in part, from redox cycling or E2 metabolites. We hypothesize that oxidative DNA adducts induced by the estrogen, E2 can be inhibited by intervention with known or potential cancer chemopreventive agents of antioxidant potential. Our main objective is to identify effective antioxidants to inhibit E2-mediated oxidative DNA damage. Specifically, 1) To determine the efficacy of known or potential chemopreventive agents for their antioxidant potential in vitro against oxidative DNA adducts induced non-enzymatically and enzymatically. 2) To determine the efficacy of selected agents to inhibit oxidative DNA adducts using E2-rat mammary carcinogenesis model. Data resulting from this project will formulate the basis of detailed investigations (RO1 grant) to correlate intermediate biomarkers (oxidative DNA damage, DNA repair activity, apoptosis, gene mutations and cell proliferation) with the disease endpoint at different intervals of rat mammary tumorigenesis. Studies can subsequently be planned with human subjects. Thus, the intermediate biomarker approach may ultimately identify women who may be at higher risk of developing breast cancer, before the onset of pathologically detectable lesions.
| Spencer, Wendy A; Vadhanam, Manicka V; Jeyabalan, Jeyaprakash et al. (2012) Oxidative DNA damage following microsome/Cu(II)-mediated activation of the estrogens, 17?-estradiol, equilenin, and equilin: role of reactive oxygen species. Chem Res Toxicol 25:305-14 |
| Aiyer, Harini S; Srinivasan, Cidambi; Gupta, Ramesh C (2008) Dietary berries and ellagic acid diminish estrogen-mediated mammary tumorigenesis in ACI rats. Nutr Cancer 60:227-34 |
