The longer women are exposed to estrogens the higher the risk of developing hormone-dependent cancers. The mechanisms of estrogen carcinogenesis are not understood. The central hypothesis of this project is that botanical dietary supplements may act as chemopreventive agents against estrogen carcinogenesis by blocking key critical steps in the estrogen genotoxicity pathway. o-Quinones are known metabolites of estrogens and they cause DNA damage. The strategy of the proposed project will be to investigate the relative abilities of popular botanicals (black cohosh, red clover, hops, dang gui, licorice, valerian, vitex) to modulate estrogen carcinogenesis. The following specific aims are proposed: 1. What is the effect of botanicals on key steps in the estrogen carcinogenesis pathway? Metabolism of estrogens will be studied in MCF-10A/12A cells. The relative ability ofthe botanical extracts to induce/inhibit key metabolic pathways will be assessed by quantifying estrogen metabolites and assessing the effect of botanicals on enzymatic gene and protein expression levels. Similar experiments will be conducted in vivo using the ACI rat model (Aim 3) and with urine samples from our recentiy completed clinical trial. 2. What is the effect of botanicals on estrogen induced DNA damage and resulting malignant transfomnation of normal breast epithelial cells? We will evaluate the effect of botanicals on DNA adduct formation in MCF-10A/10F cells and correlate the expected reduction in DNA adducts with inhibition of estrogen induced malignant transformation. DNA adducts will also be analyzed in the ACI rat model (Aim 3) and in human urine samples from our clinical trial. 3. What is the effect of botanicals on estrogen carcinogenesis in vivo? ACI rats will be treated with estradiol pellets and botanicals identified from Aims 1 and 2 with significant effects on key estrogen carcinogenesis pathways will be administered in the diet. Urinary metabolites and DNA adducts will be collected and analyzed. For botanicals which show significant modulation of estrogen DNA adducts, a long-term carcinogenesis experiment will be performed. Modulation of tumor incidence relative to control diet will be analyzed.
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