Dietary Administration of δ- and γ-Tocopherol Inhibits Tumorigenesis in the Animal Model of Estrogen Receptor-Positive, but not HER-2 Breast Cancer

Tocopherol, a member of the vitamin E family, consists of four forms designated as alpha, beta, gamma, and delta. Several large cancer prevention studies with alpha-tocopherol have reported no beneficial results, but recent laboratory studies have suggested that delta- and gamma-tocopherol may be more effective. In two different animal models of breast cancer, the chemopreventive activities of individual tocopherols were assessed using diets containing 0.3% of tocopherol (alpha-, delta-, or gamma-) or 0.3% of a gamma-tocopherol rich mixture (gamma-TmT). Although administration of tocopherols did not prevent human epidermal growth factor receptor 2 (HER2/neu)-driven tumorigenesis, delta- and gamma-tocopherols inhibited hormone-dependent mammary tumorigenesis in N-methyl-N-nitrosourea (NMU)-treated female Sprague-Dawley rats. NMU-treated rats showed an average tumor burden of 10.6 +/- 0.8 g in the control group at 11 weeks, whereas dietary administration of delta- and gamma-tocopherols significantly decreased tumor burden to 7.2 +/- 0.8 g (P < 0.01) and 7.1 +/- 0.7 g (P < 0.01), respectively. Tumor multiplicity was also reduced in delta- and gamma-tocopherol treatment groups by 42% (P < 0.001) and 32% (P < 0.01), respectively. In contrast, alpha-tocopherol did not decrease tumor burden or multiplicity. In mammary tumors, the protein levels of proapoptotic markers (BAX, cleaved caspase-9, cleaved caspase-3, cleaved PARP) were increased, whereas antiapoptotic markers (Bcl-2, XIAP) were inhibited by delta-tocopherol, gamma-tocopherol, and gamma-TmT. Furthermore, markers of cell proliferation (PCNA, PKC alpha), survival (PPAR-gamma, PTEN, phospho-Akt), and cell cycle (p53, p21) were affected by delta- and gamma-tocopherols. Both delta- and gamma-tocopherols, but not alpha-tocopherol, seem to be promising agents for the prevention of hormone-dependent breast cancer. Cancer Prev Res; 5(11); 1310-20. (C) 2012 AACR.