Abstract 243: Tocopherols inhibit oxidative and nitrosative stress in estrogen-induced early mammary hyperplasia in ACI rats

Abstract

Abstract Tocopherols (T), members of the vitamin E family, exist in four different forms designated as α, β, δ and γ. Due to their antioxidant properties, tocopherols are suggested to reduce the risk of cancer. α-T is known as the classic vitamin E as it is the major tocopherol found in plasma and tissues. However, some large scale clinical trials with α-T have provided inconclusive results. Recent studies from our laboratory and others indicate that δ-T and γ-T have stronger anti-cancer activities than α-T in vitro and in vivo. γ-T is the most common form of vitamin E in the U.S. diet, present in vegetable oils such as soybean, corn and cottonseed. The naturally occurring γ-T-enriched mixture of tocopherols (γ-TmT) has been reported to inhibit mammary tumorigenesis in estrogen receptor positive models of breast cancer. Using ACI rats, we investigated the chemopreventive activity of γ-TmT in the early stages of estrogen-induced mammary tumorigenesis. ACI rats provide an established model of rodent mammary carcinogenesis due to their high sensitivity to estrogen. Rats were subcutaneously implanted with 9 mg of 17β-estradiol (E2) in silastic tubings and fed with 0.3% γ-TmT diet for 1, 3, 7 and 14 days. Administration of γ-TmT gradually increased the levels of tocopherols and their metabolites in the serum and mammary glands of the rats from day 1 to 14. Histological analysis showed that estrogen induced mammary hyperplasia starting at day 3. However, the induction of mammary hyperplasia was not altered by dietary γ-TmT. Interestingly, mRNA expression of PPARγ, a nuclear receptor which inhibits cell proliferation and survival, was significantly increased by γ-TmT administration at 14 days. The oxidative and nitrosative stress markers, 8-oxo-dG and nitrotyrosine, respectively, were induced in the mammary tissues of E2-treated rats as early as day 1. γ-TmT decreased the levels of these markers starting from day 7. Serum level of 8-isoprostane, a marker of oxidative stress, was also decreased by γ-TmT. Elevated mRNA levels of a transcription factor Nrf2 and its downstream antioxidant enzymes, superoxide dismutase, catalase and glutathione peroxidase, were observed in the γ-TmT fed groups as early as day 1, indicating the induction of antioxidant response by γ-TmT. In conclusion, inhibition of oxidative, nitrosative stress and stimulation of antioxidant response are the primary effects of γ-TmT administration in the early stages of E2-induced mammary tumorigenesis in ACI rats. Citation Format: Soumyasri Das Gupta, Jae Young So, Joseph Wahler, Mao-Jung Lee, Chung S. Yang, Nanjoo Suh. Tocopherols inhibit oxidative and nitrosative stress in estrogen-induced early mammary hyperplasia in ACI rats. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 243. doi:10.1158/1538-7445.AM2014-243