Inhibitory Effects of γ- and δ-Tocopherols on Estrogen-Stimulated Breast Cancer In Vitro and In Vivo

Estrogens have been implicated as complete carcinogens for breast and other tissues through mechanisms involving increased cell proliferation, oxidative stress, and DNA damage. Because of their potent antioxidant activity and other effects, tocopherols have been shown to exert antitumor activities in various cancers. However, limited information is available on the effect of different forms of tocopherols in estrogen-mediated breast cancer. To address this, we examined the effects of alpha-, gamma-, and delta-tocopherols as well as a natural gamma-tocopherol-rich mixture of tocopherols, gamma-TmT, on estrogen-stimulated MCF-7 cells in vitro and in vivo. For the in vivo studies, MCF-7 cells were injected into the mammary fat pad of immunodeficient mice previously implanted with estrogen pellets. Mice were then administered diets containing 0.2% alpha-, gamma-, delta-tocopherol, or gamma-TmT for 5 weeks. Treatment with alpha-, gamma-, delta-tocopherols, and gamma-TmT reduced tumor volumes by 29% (P < 0.05), 45% (P < 0.05), 41% (P < 0.05), and 58% (P < 0.01), as well as tumor weights by 20%, 37% (P < 0.05), 39% (P < 0.05), and 52% (P < 0.05), respectively. gamma- and delta-tocopherols and gamma-TmT inhibited the expression of cell proliferation-related genes such as cyclin D1 and c-Myc, and estrogen-related genes such as TFF/pS2, cathepsin D, and progesterone receptor in estrogen- stimulated MCF-7 cells in vitro. Further, gamma-and delta-tocopherols decreased the levels of estrogen-induced oxidative stress and nitrosative stress markers, 8-hydroxy-2'-deoxyguanosine and nitrotyrosine, as well as the DNA damage marker, gamma-H2AX. Our results suggest that g-and d-tocopherols and the gamma-tocopherol-rich mixture are effective natural agents for the prevention and treatment of estrogen-mediated breast cancer. (C) 2017 AACR.