Epidemiological studies provide convincing evidence for an inverse relation between quantities of fruit and vegetables consumed and the risk of developing cancer. Cruciferous vegetable (e.g., broccoli) consumption has been recently associated with reduced risk for breast cancer. A major mechanism for protection against carcinogenesis involves induction of phase 2 detoxication enzymes that promote elimination of carcinogens and boost antioxidant capacity. Many edible plants, most notably 3-day-old broccoli sprouts, contain potent phase 2 enzyme inducer activity in the form of isothiocyanates or their glucosinolate precursors. In animals, sulforaphane, derived from the principal glucosinolate (glucoraphanin) of broccoli sprouts, is a very potent inducer of phase 2 enzyme activity and protects against chemical carcinogenesis. The objective of this study is to translate and evaluate these laboratory findings in a human population at elevated risk for breast cancer. Previous trials have afforded important information on the safety, metabolism, and urinary disposition of isothiocyanates, and on the activation of glucosinolates. Therefore, our aims are to 1) determine the pharmacodynamic action of a broccoli sprouts preparation, as well as pure sulforaphane and pure glucoraphanin, in the mammary epithelium of rodents to develop better biomarkers;2) evaluate the pharmacokinetics and pharmacodynamic action of broccoli sprouts in 30 healthy women undergoing breast reduction surgery or prophylactic mastectomy by conducting a 10-day randomized placebo controlled clinical trial that measures isothiocyanate levels in blood, urine and mammary tissue as well as phase 2 inducer activity, mRNA transcript levels and estrogen metabolites in mammary tissue;and 3) test whether a 3 month intervention of a broccoli sprout preparation modulates a panel of breast cancer risk biomarkers (Ki67 expression, estrogen metabolite profiles, novel markers) compared to placebo in 126 women at increased risk for breast cancer using a Phase II randomized clinical trial design. These studies will provide a rigorous assessment of the usefulness of modulating expression of carcinogen detoxication enzymes and other sulforaphane target genes by means of a food containing a standardized level of a phytochemical as a general strategy for chemoprevention in humans
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