Dietary tocopherols inhibit cell proliferation, regulate expression of ERα, PPARγ, and Nrf2, and decrease serum inflammatory markers during the development of mammary hyperplasia
Article first published online: 2 MAR 2012
Copyright © 2012 Wiley Periodicals, Inc.
Volume 52, Issue 7, pages 514–525, July 2013
How to Cite
Smolarek, A. K., So, J. Y., Thomas, P. E., Lee, H. J., Paul, S., Dombrowski, A., Wang, C.-X., Saw, C. L.-L., Khor, T. O., Kong, A.-N. T., Reuhl, K., Lee, M.-J., Yang, C. S. and Suh, N. (2013), Dietary tocopherols inhibit cell proliferation, regulate expression of ERα, PPARγ, and Nrf2, and decrease serum inflammatory markers during the development of mammary hyperplasia. Mol. Carcinog., 52: 514–525. doi: 10.1002/mc.21886
- Issue published online: 18 JUN 2013
- Article first published online: 2 MAR 2012
- Manuscript Revised: 26 JAN 2012
- Manuscript Accepted: 26 JAN 2012
- Manuscript Received: 8 SEP 2011
- vitamin E;
- breast cancer;
- estrogen receptor;
- peroxisome proliferator-activated receptor γ
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.