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Dietary tocopherols inhibit cell proliferation, regulate expression of ERα, PPARγ, and Nrf2, and decrease serum inflammatory markers during the development of mammary hyperplasia

Authors

  • Amanda K. Smolarek,

    1. Department of Pharmacology and Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
    2. Department of Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
    3. Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
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  • Jae Young So,

    1. Department of Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
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  • Paul E. Thomas,

    1. Department of Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
    2. Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
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  • Hong Jin Lee,

    1. Department of Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
    2. Department of Food Science and Technology, Chung-Ang University, Anseong, South Korea
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  • Shiby Paul,

    1. Department of Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
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  • Anne Dombrowski,

    1. Department of Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
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  • Chung-Xiou Wang,

    1. Department of Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
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  • Constance Lay-Lay Saw,

    1. Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, New Jersey
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  • Tin Oo Khor,

    1. Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, New Jersey
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  • Ah-Ng Tony Kong,

    1. Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, New Jersey
    2. The Cancer Institute of New Jersey, New Brunswick, New Jersey
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  • Kenneth Reuhl,

    1. Department of Pharmacology and Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
    2. Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
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  • Mao-Jung Lee,

    1. Department of Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
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  • Chung S. Yang,

    1. Department of Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
    2. Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
    3. The Cancer Institute of New Jersey, New Brunswick, New Jersey
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  • Nanjoo Suh

    Corresponding author
    1. Department of Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
    2. Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
    3. The Cancer Institute of New Jersey, New Brunswick, New Jersey
    • Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854.
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Abstract

Previous clinical and epidemiological studies of vitamin E have used primarily α-tocopherol for the prevention of cancer. However, γ-tocopherol has demonstrated greater anti-inflammatory and anti-tumor activity than α-tocopherol in several animal models of cancer. This study assessed the potential chemopreventive activities of a tocopherol mixture containing 58% γ-tocopherol (γ-TmT) in an established rodent model of mammary carcinogenesis. Female ACI rats were utilized due to their sensitivity to 17β-estradiol (E2) to induce mammary hyperplasia and neoplasia. The rats were implanted subcutaneously with sustained release E2 pellets and given dietary 0.3% or 0.5% γ-TmT for 2 or 10 wk. Serum E2 levels were significantly reduced by the treatment with 0.5% γ-TmT. Serum levels of inflammatory markers, prostaglandin E2 and 8-isoprostane, were suppressed by γ-TmT treatment. Histology of mammary glands showed evidence of epithelial hyperplasia in E2-treated rats. Immunohistochemical analysis of the mammary glands revealed a decrease in proliferating cell nuclear antigen (PCNA), cyclooxygenase-2 (COX-2), and estrogen receptor α (ERα), while there was an increase in cleaved-caspase 3, peroxisome proliferator-activated receptor γ (PPARγ), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in γ-TmT-treated rats. In addition, treatment with γ-TmT resulted in a decrease in the expression of ERα mRNA, whereas mRNA levels of ERβ and PPARγ were increased. In conclusion, γ-TmT was shown to suppress inflammatory markers, inhibit E2-induced cell proliferation, and upregulate PPARγ and Nrf2 expression in mammary hyperplasia, suggesting that γ-TmT may be a promising agent for human breast cancer prevention. © 2012 Wiley Periodicals, Inc.

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