Dietaryγ-Tocopherol Rich Mixture Inhibits Estrogen-Induced Mammary Tumorigenesis by Modulating Estrogen Metabolism, Antioxidant Response and PPARγ.
Cancer Prev Res (Phila). 2015 Jun 30. Epub 2015 Jun 30. PMID: 26130252
Soumyasri Das Gupta
This study evaluated the anti-cancer activity and mechanism of action of aγ-tocopherol rich tocopherol mixture, γ-TmT, in two different animal models of estrogen-induced breast cancer. The chemopreventive effect of γ-TmT at early (6 weeks), intermediate (18 weeks) and late (31 weeks) stages of mammary tumorigenesis was determined using the ACI rat model. Female rats receiving 17β-estradiol (E2) implants were administered with different doses (0, 0.05%, 0.1%, 0.3% and 0.5%) of γ-TmT diet. Treatment with 0.3% and 0.5% γ-TmT decreased tumor volume and multiplicity. At 31 weeks, serum concentrations of E2 were significantly decreased by γ-TmT. γ-TmT preferentially induced expression of the E2 metabolizing enzyme CYP1A1, over CYP1B1 in the rat mammary tissues. Nrf2-dependent antioxidant response was stimulated by γ-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 γ-TmT treated groups. Treatment with γ-TmT increased expression of PPARγ and its downstream genes, PTEN and p27, while the cell proliferation marker, PCNA, was significantly reduced in γ-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, γ-TmT inhibited E2-dependent tumor growth at all the doses tested. In conclusion, γ-TmT reduced mammary tumor development, in part through decreased E2 availability and reduced oxidative stress in mammary tissues; γ-TmT could thus be an effective agent for the prevention and treatment of E2-induced breast cancer.