: Tocotrienols, a subclass of compounds in the vitamin E family, significantly inhibits mitogen-induced proliferation and initiates apoptosis in preneoplastic and neoplastic mammary epithelial cells. These findings are particularly interesting because they were observed using treatment doses that had little or no effect on normal mammary epithelial cells growth or viability. In contrast, studies investigating the anticancer activity of tocopherols, the other vitamin E subclass, have shown for the most part, negative results. Determining the mechanism(s) mediating the antiproliferative and apoptotic effects of tocotrienols would provide essential information necessary for understanding the potential health benefits of these compounds in preventing and/or reducing the risk of breast cancer in women. The following aims are designed to determine the mechanism(s) mediating the antiproliferative and apoptotic effects of tocotrienols in normal and neoplastic mammary epithelial cells, with the goal of providing useful insights for basing effective strategies for use of tocotrienols in the prevention and treatment of breast cancer in women. 1) To determmentionedine tissue distribution and cellular concentrations of specific tocotrienols and correlate these findings with treatment effects on mitogenesis and apoptosis in normal, preneoplastic and neoplastic mammary epithelial cells in animals fed tocotrienol-supplemented diets. Absorption and distribution of tocopherols and tocotrienols is limited by the specificity and saturability of specific carrier protein and transport mechanisms within the body; 2) To determine the intracellular mechanism(s) mediating tocotrienol suppression of EGF-dependent mitogenic signaling in isolated normal, preneoplastic and neoplastic mammary epithelial cells in vitro. Since the initial events associated with EGF-dependent mitogenesis in mammary epithelial cells include protein kinase C, adenylate cyclase and cAMP-dependent protein activation, and tocotrienols have been shown to inhibit activation of these proteins in other cells types, it is possible that the antiproliferative effects of tocotrienols results from the inhibition of these mitogenic-signaling pathways; 3) To determine the intracellular signaling pathways responsible for mediating tocotrienol-induced apoptosis in normal, preneoplastic and neoplastic mammary epithelial cells. Various signaling pathways mediate vitamin E-dependent apoptosis in different cell types. Studies will be conducted to identify those apoptotic signaling pathways involved in tocotrienol-induced apoptosis, and whether or not similar signaling pathways are involved in mediating tocotrienol-induced apoptosis in, preneoplastic and neoplastic mammary epithelial cells.
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