Dietary -Tocopherol-Rich Mixture Inhibits Estrogen-Induced Mammary Tumorigenesis by Modulating Estrogen Metabolism, Antioxidant Response, and PPAR.
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This study evaluated the anticancer activity and mechanism of action of a -tocopherol-rich tocopherol mixture, -TmT, in two different animal models of estrogen-induced breast cancer. The chemopreventive effect of -TmT at early (6 weeks), intermediate (18 weeks), and late (31 weeks) stages of mammary tumorigenesis was determined using the August-Copenhagen Irish rat model. Female rats receiving 17-estradiol (E2) implants were administered with different doses (0%, 0.05%, 0.1%, 0.3%, and 0.5%) of -TmT diet. Treatment with 0.3% and 0.5% -TmT decreased tumor volume and multiplicity. At 31 weeks, serum concentrations of E2 were significantly decreased by -TmT. -TmT preferentially induced expression of the E2-metabolizing enzyme CYP1A1, over CYP1B1 in the rat mammary tissues. Nrf2-dependent antioxidant response was stimulated by -TmT, as evident from enhanced expression of its downstream targets, NQO1, GCLM, and HMOX1. Serum concentrations of the oxidative stress marker, 8-isoprostane, were also decreased in the -TmT-treated groups. Treatment with -TmT increased expression of PPAR and its downstream genes, PTEN and p27, whereas the cell proliferation marker, PCNA, was significantly reduced in -TmT-treated mammary tumors. In an orthotopic model in which human MCF-7 breast cancer cells were injected into the mammary fat pad of immunodeficient mice, -TmT inhibited E2-dependent tumor growth at all the doses tested. In conclusion, -TmT reduced mammary tumor development, in part through decreased E2 availability and reduced oxidative stress in mammary tissues; -TmT could thus be an effective agent for the prevention and treatment of E2-induced breast cancer.
