Dietary γ-Tocopherol-Rich Mixture Inhibits Estrogen-Induced Mammary Tumorigenesis by Modulating Estrogen Metabolism, Antioxidant Response, and PPARγ

This study evaluated the anticancer activity and mechanism of action of a gamma-tocopherol-rich tocopherol mixture, gamma-TmT, in two different animal models of estrogen-induced breast cancer. The chemopreventive effect of gamma-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 beta-estradiol (E2) implants were administered with different doses (0%, 0.05%, 0.1%, 0.3%, and 0.5%) of gamma-TmT diet. Treatment with 0.3% and 0.5% gamma-TmT decreased tumor volume and multiplicity. At 31 weeks, serum concentrations of E2 were significantly decreased by gamma-TmT. gamma-TmT preferentially induced expression of the E2-metabolizing enzyme CYP1A1, over CYP1B1 in the rat mammary tissues. Nrf2-dependent antioxidant response was stimulated by gamma-TmT, as evident from enhanced expression of its downstreamtargets, NQO1, GCLM, and HMOX1. Serum concentrations of the oxidative stress marker, 8-isoprostane, were also decreased in the gamma-TmT-treated groups. Treatment with gamma-TmT increased expression of PPAR gamma and its downstream genes, PTEN and p27, whereas the cell proliferation marker, PCNA, was significantly reduced in gamma-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, gamma-TmT inhibited E2-dependent tumor growth at all the doses tested. In conclusion, gamma-TmT reduced mammary tumor development, in part through decreased E2 availability and reduced oxidative stress in mammary tissues; gamma-TmT could thus be an effective agent for the prevention and treatment of E2-induced breast cancer. (C) 2015 AACR.