The overall objectives of this application are to study further quercetin's efficacy as a chemopreventive agent, and to investigate its mechanism of action. In animal studies, quercetin significantly inhibited the incidence and multiplicity of dimethylbenz(alpha)anthracene(DMBA)- and N- nitrosomethylurea-induced mammary cancers in rats and colon tumors in mice. Additionally, certain flavonoids including quercetin inhibit tumor promotion by l2-O-tetradecanoyl-phorbol-l3-acetate in the two stage carcinogenesis in mouse epidermis. Quercetin also inhibits DHBA-induced mammary lesions in a mouse mammary gland organ culture system, developed in our laboratory. The mechanism involved in the inhibition of carcinogenesis by quercetin is unclear. Four fundamental enzymes involved in the signal transduction pathway have been reported to be inhibited by quercetin: protein kinase C, protein tyrosine kinase, lipoxygenase, and topoisomerase II. Monitoring the activities of some of these enzymes and their substrates in rat mammary glands during carcinogenesis and chemoprevention will provide a better understanding of the in vivo mode of action of this compound. These mechanistic studies may also lead to the identification of other agents that may enhance the efficacy of quercetin in preventing mammary tumors. We propose to: 1. clarify further the chemopreventive action of quercetin in a DMBA- induced mammary cancer model, 2. examine whether quercetin inhibits the initiation and/or promotion phases of carcinogenesis, 3. determine whether its effect is selective against the development of hormone-dependent or -independent tumors, and 4. evaluate the role of quercetin's enzyme-altering effects in carcinogenesis.
