Differential gene regulation and tumor inhibitory activities of alpha-, delta- and gamma-tocopherols in estrogen-mediated mammary carcinogenesis

Despite experimental evidence elucidating the anti-tumor activities of tocopherols, clinical trials with α-tocopherol (α-T) have failed to demonstrate its beneficial effects in cancer prevention. This study compared the chemopreventive efficacy of individual tocopherols (α-, -, -T) and a -T rich tocopherol mixture (-TmT) in the August Copenhagen Irish (ACI) rat model of estrogen-mediated mammary cancer. Female ACI rats receiving 17β-estradiol (E2) implants were administered with 0.2% α-T, -T, -T or -TmT for 30 weeks. While α-T had no significant effects on mammary tumor growth in ACI rats, -T, -T and -TmT reduced mammary tumor volume by 51% (p < 0.05), 60% (p < 0.01) and 59% (p < 0.01), respectively. Immunohistochemical analysis revealed that -T, -T and -TmT reduced levels of the cell proliferation marker, PCNA, 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 -T induced robust gene expression changes in the mammary tumors of ACI rats. IPA analysis identified 'Cancer' as a top disease pathway and 'Tumor growth' and 'Metastasis' as the top signaling pathways modulated by -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. -T, -T and -TmT could be promising agents for the prevention of estrogen-mediated mammary carcinogenesis. -T suppressed growth of mammary tumors most effectively in ACI rats.

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