title: Dietary tocopherols inhibit cell proliferation, regulate expression of ERα, PPARγ, and Nrf2, and decrease serum inflammatory markers during the development of mammary hyperplasia.
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.
authors.affiliation: Department of Pharmacology and Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Smolarek
authors.forename: Jae Young
authors.initials: JY
authors.lastname: So
authors.forename: Paul E
authors.initials: PE
authors.lastname: Thomas
authors.forename: Hong Jin
authors.initials: HJ
authors.lastname: Lee
authors.forename: Shiby
authors.initials: S
authors.lastname: Paul
authors.forename: Anne
authors.initials: A
authors.lastname: Dombrowski
authors.forename: Chung-Xiou
authors.initials: CX
authors.lastname: Wang
authors.forename: Constance Lay-Lay
authors.initials: CL
authors.lastname: Saw
authors.forename: Tin Oo
authors.initials: TO
authors.lastname: Khor
authors.forename: Ah-Ng Tony
authors.initials: AN
authors.lastname: Kong
authors.forename: Kenneth
authors.initials: K
authors.lastname: Reuhl
authors.forename: Mao-Jung
authors.initials: MJ
authors.lastname: Lee
authors.forename: Chung S
authors.initials: CS
authors.lastname: Yang
authors.forename: Nanjoo
authors.initials: N
authors.lastname: Suh
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D004032:Diet; D004958:Estradiol / Q000097:blood; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D007124:Immunoenzyme Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008862:Microsomes, Liver / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011912:Rats, Inbred ACI; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D024505:Tocopherols / Q000008:administration & dosage* / Q000097:blood
chemical_list: D000975:Antioxidants; D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; D018836:Inflammation Mediators; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D047495:PPAR gamma; D012333:RNA, Messenger; D004958:Estradiol; D024505:Tocopherols