Abstract
Despite experimental evidence elucidating the antitumor activities of tocopherols, clinical trials with a-tocopherol (alpha-T) have failed to demonstrate its beneficial effects in cancer prevention. This study compared the chemopreventive efficacy of individual tocopherols (alpha-, delta-, and gamma-T) and a gamma-T-rich tocopherol mixture (gamma-TmT) in the August-Copenhagen Irish (ACI) rat model of estrogen-mediated mammary cancer. Female ACI rats receiving 17 beta-estradiol (E2) implants were administered with 0.2% alpha-T, delta-T, gamma-T, or gamma-TmT for 30 weeks. Although alpha-T had no significant effects onmammarytumor growth in ACI rats, delta-T, gamma-T, and gamma-TmT reduced mammary tumor volume by 51% (P < 0.05), 60% (P < 0.01), and 59% (P < 0.01), respectively. Immunohistochemical analysis revealed that delta-T, gamma-T, and gamma-TmT reduced levels of the cell proliferation marker, proliferating cell nuclear antigen, in the rat mammary tumors. To gain further insight into the biological functions of different forms of tocopherols, RNA-seq analysis of the tumors was performed. Treatment with gamma-T induced robust gene expression changes in the mammary tumors of ACI rats. Ingenuity Pathway Analysis identified "Cancer" as a top disease pathway and "Tumor growth" and "Metastasis" as the top signaling pathways modulated by gamma-T. Although the results need further functional validation, this study presents an unbiased attempt to understand the differences between biological activities of individual forms of tocopherols at the whole transcriptome level. In conclusion, delta-T and gamma-T have superior cancer preventive properties compared to alpha-T in the prevention of estrogen-mediated mammary carcinogenesis. (C) 2017 AACR.