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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
Author(s) -
Smolarek Amanda K.,
So Jae Young,
Thomas Paul E.,
Lee Hong Jin,
Paul Shiby,
Dombrowski Anne,
Wang ChungXiou,
Saw Constance LayLay,
Khor Tin Oo,
Kong AhNg Tony,
Reuhl Kenneth,
Lee MaoJung,
Yang Chung S.,
Suh Nanjoo
Publication year - 2013
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.21886
Subject(s) - endocrinology , medicine , hyperplasia , proliferating cell nuclear antigen , peroxisome proliferator activated receptor , biology , inflammation , vitamin e , carcinogenesis , estrogen receptor , estrogen , downregulation and upregulation , immunohistochemistry , receptor , cancer , breast cancer , antioxidant , biochemistry , gene
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 (E 2 ) to induce mammary hyperplasia and neoplasia. The rats were implanted subcutaneously with sustained release E 2 pellets and given dietary 0.3% or 0.5% γ‐TmT for 2 or 10 wk. Serum E 2 levels were significantly reduced by the treatment with 0.5% γ‐TmT. Serum levels of inflammatory markers, prostaglandin E 2 and 8‐isoprostane, were suppressed by γ‐TmT treatment. Histology of mammary glands showed evidence of epithelial hyperplasia in E 2 ‐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 E 2 ‐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.