Dietary Isothiocyanates in Cancer Prevention: Effects of Estrogen Metabolism

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DESCRIPTION (provided by applicant): There is a crucial need for breast cancer prevention. Isothiocyanates (ITCs) are dietary constituents present predominantly in cruciferous vegetables present in the diet, and investigated for their chemopreventive properties, particularly against carcinogen-induced tumorigenesis in rodent models. Additionally, ITCs are constituents of numerous herbal supplements including Daily Cruciferous Plus, Broccoli Sprouts, and BioBasics, among others. Consumption of cruciferous vegetables is inversely associated with the risk of cancer of the lung, colon, stomach and prostate, and has been reported to lower the risk of breast cancer by as much as 20-40% in post-menopausal women. Our preliminary data indicates that exposure to phenethyl ITC or sulforaphane lowers 17beta-estradiol concentrations in human breast cancer MCF-7 cells and oral phenethyl ITC administration to rats produces decreased liver estradiol concentrations. Our hypothesis is that dietary ITCs represent effective preventive agents in breast cancer, and one mechanism of action contributing to their breast cancer preventive effect is their alteration of 17beta-estradiol concentrations in plasma and tissues, including mammary tissue. In this application we will examine one of the major dietary ITCs, phenethyl ITC (PEITC). The specific aims of this application are: (1) To determine the concentration- and time-dependent effects of PEITC on estradiol and estradiol conjugates in rat liver and mammary tissue, and on sulfate and glucuronide conjugation activities. Our hypothesis is that PEITC at low concentrations will decrease estradiol concentrations, with the mechanism predominantly due to induction of Phase II (conjugative) metabolism. (2) To determine the dose-dependent effects of PEITC on (a) the tumor frequency, size and latency and (b) estrogen and estrogen metabolite concentrations in an estrogen-dependent animal breast cancer model, N-methyl-N-nitrosourea (NMU)-induced carcinogenesis in rats. Some rats will be treated with17beta-estradiol to reverse the effects of PEITC on estrogen metabolism. The proposed studies will provide preliminary information on ITC-mediated effects on estradiol metabolism, as one potential mechanism underlying the breast cancer preventive effects of ITCs: this mechanism has not previously been investigated for ITCs. Since dietary compounds are not perceived as "drugs", and are not associated with toxicity, the use of dietary isothiocyanates represents an approach for chemoprevention that may be widely- acceptable by healthy individuals.