Abstract 2797: Dietary administration of a γ-tocopherol rich mixture of tocopherols inhibits estrogen-mediated mammary tumorigenesis

Abstract

Tocopherols (T), members of the vitamin E family, occur in four forms designated as α, β, δ and γ. Tocopherols are suggested to reduce the risk of cancer. α-T is the predominant form of tocopherols found in human tissues. However, clinical studies with α-T have provided inconclusive results. γ-T is our major dietary source of tocopherols. Recent studies have demonstrated that γ-T has higher anti-cancer activity than α-T in animal models of cancer. This study investigated the cancer preventive activity of a naturally occurring γ-T rich mixture of tocopherols (γ-TmT) in two different in vivo models of estrogen receptor (ER)-positive breast cancer, namely estrogen supplemented August-Copenhagen Irish (ACI) rats and MCF-7 xenograft tumor mouse models. ACI rats were subcutaneously implanted with 9 mg of 17β-estradiol (E2) in silastic tubings and administered with diets containing 0.05%, 0.1%, 0.3% and 0.5% γ-TmT. Rats were euthanized at early (6 weeks), intermediate (18 weeks) and late (31 weeks) stages of E2-induced mammary carcinogenesis. Treatment with 0.3% and 0.5% γ-TmT reduced the tumor volume by 51% (p<0.01) and 41% (p<0.01), respectively while the lower doses of γ-TmT (0.05% and 0.1%) were not effective. Tumor multiplicity was also reduced by 38% (p<0.02) and 32% (p<0.02) in the 0.3% and 0.5% γ-TmT treatment groups, respectively. Dietary γ-TmT increased the levels of tocopherols and their metabolites in the serum. Serum levels of E2 were significantly lowered in the 0.3% and 0.5% γ-TmT administered groups. Analysis of mammary glands and tumors revealed that γ-TmT led to induced mRNA expression of the estrogen metabolizing enzyme, CYP1A1 at each experimental time point. CYP1A1 metabolizes E2 to its non-carcinogenic metabolite, 2-hydroxyestradiol. Gene expression of the Nrf2 mediated phase II detoxification enzymes NQO1, GCLM, UGT1A1, COMT and the antioxidant enzyme heme oxygenase were also upregulated in the γ-TmT treated groups. Thus, γ-TmT exerts its protective activity in E2-induced mammary carcinogenesis by lowering the levels of available E2 through increased metabolism of E2 and simultaneous removal of E2 metabolites through induction of the antioxidant response pathway. mRNA levels of PPARγ, a nuclear receptor which inhibits cell proliferation was also induced in the 0.3% and 0.5% γ-TmT treated groups. In a second in vivo model, the ER positive breast cancer cell line, MCF-7 was utilized. Mice were injected with MCF-7 cells after implantation of E2 pellets. Effect of the different doses of dietary γ-TmT (0.05%, 0.1%, 0.3% and 0.5%) treatment on the mammary xenograft tumors was studied. A significant reduction in the volume and weight of mammary tumors was observed in each of the γ-TmT treatment groups. In conclusion, γ-TmT inhibits mammary tumorigenesis in two different in vivo models of E2-induced breast cancer and could be a potential safe, natural agent for the chemoprevention of ER-positive breast cancer.

Citation Format: Soumyasri Das Gupta, Sudathip Sae-tan, Joseph Wahler, Jae Young So, Larry C. Cheng, Min Ji Bak, Mao-Jung Lee, Yong Lin, Weichung Joe Shih, Chung S Yang, Nanjoo Suh. Dietary administration of a γ-tocopherol rich mixture of tocopherols inhibits estrogen-mediated mammary tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2797. doi:10.1158/1538-7445.AM2015-2797