title: Dietary γ-Tocopherol-Rich Mixture Inhibits Estrogen-Induced Mammary Tumorigenesis by Modulating Estrogen Metabolism, Antioxidant Response, and PPARγ.
abstract: This study evaluated the anticancer activity and mechanism of action of a γ-tocopherol-rich tocopherol mixture, γ-TmT, in two different animal models of estrogen-induced breast cancer. The chemopreventive effect of γ-TmT at early (6 weeks), intermediate (18 weeks), and late (31 weeks) stages of mammary tumorigenesis was determined using the August-Copenhagen Irish rat model. Female rats receiving 17β-estradiol (E2) implants were administered with different doses (0%, 0.05%, 0.1%, 0.3%, and 0.5%) of γ-TmT diet. Treatment with 0.3% and 0.5% γ-TmT decreased tumor volume and multiplicity. At 31 weeks, serum concentrations of E2 were significantly decreased by γ-TmT. γ-TmT preferentially induced expression of the E2-metabolizing enzyme CYP1A1, over CYP1B1 in the rat mammary tissues. Nrf2-dependent antioxidant response was stimulated by γ-TmT, as evident from enhanced expression of its downstream targets, NQO1, GCLM, and HMOX1. Serum concentrations of the oxidative stress marker, 8-isoprostane, were also decreased in the γ-TmT-treated groups. Treatment with γ-TmT increased expression of PPARγ and its downstream genes, PTEN and p27, whereas the cell proliferation marker, PCNA, was significantly reduced in γ-TmT-treated mammary tumors. In an orthotopic model in which human MCF-7 breast cancer cells were injected into the mammary fat pad of immunodeficient mice, γ-TmT inhibited E2-dependent tumor growth at all the doses tested. In conclusion, γ-TmT reduced mammary tumor development, in part through decreased E2 availability and reduced oxidative stress in mammary tissues; γ-TmT could thus be an effective agent for the prevention and treatment of E2-induced breast cancer.
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
authors.forename: Soumyasri
authors.initials: S
authors.lastname: Das Gupta
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
authors.forename: Sudathip
authors.initials: S
authors.lastname: Sae-tan
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
authors.forename: Joseph
authors.initials: J
authors.lastname: Wahler
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: So
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
authors.forename: Min Ji
authors.initials: MJ
authors.lastname: Bak
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
authors.forename: Larry C
authors.initials: LC
authors.lastname: Cheng
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
authors.forename: Mao-Jung
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Department of Biostatistics, School of Public Health, Rutgers University. Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Biostatistics, School of Public Health, Rutgers University. Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
authors.forename: Weichung Joe
authors.initials: WJ
authors.lastname: Shih
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
authors.forename: James D
authors.initials: JD
authors.lastname: Shull
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A & M University, College Station, Texas.
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey. Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
authors.forename: Chung S
authors.initials: CS
authors.lastname: Yang
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey. Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. nsuh@pharmacy.rutgers.edu.
authors.forename: Nanjoo
authors.initials: N
authors.lastname: Suh
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000737:chemistry; D004958:Estradiol / Q000008:administration & dosage; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D008321:Mammary Glands, Animal / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000517:prevention & control; D008325:Mammary Neoplasms, Experimental / Q000517:prevention & control; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D018384:Oxidative Stress; D047495:PPAR gamma / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D024504:gamma-Tocopherol / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; C493962:Cdkn1b protein, rat; D004967:Estrogens; D047495:PPAR gamma; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D050760:Cyclin-Dependent Kinase Inhibitor p27; C075750:8-epi-prostaglandin F2alpha; D004958:Estradiol; D024504:gamma-Tocopherol; D015237:Dinoprost; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat