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International Journal of Breast Cancer
Volume 2013 (2013), Article ID 101705, 17 pages
http://dx.doi.org/10.1155/2013/101705
Research Article

Mechanisms Mediating the Effects of γ-Tocotrienol When Used in Combination with PPARγ Agonists or Antagonists on MCF-7 and MDA-MB-231 Breast Cancer Cells

College of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe, LA 71209, USA

Received 12 September 2012; Revised 20 November 2012; Accepted 29 November 2012

Academic Editor: Heather E. Kleiner-Hancock

Copyright © 2013 Abhita Malaviya and Paul W. Sylvester. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

γ-Tocotrienol is a natural vitamin E that displays potent anticancer activity, and previous studies suggest that these effects involve alterations in PPARγ activity. Treatment with 0.5–6 μM  γ-tocotrienol, 0.4–50 μM PPARγ agonists (rosiglitazone or troglitazone), or 0.4–25 μM PPARγ antagonists (GW9662 or T0070907) alone resulted in a dose-responsive inhibition of MCF-7 and MDA-MB-231 breast cancer proliferation. However, combined treatment of 1–4 μM  γ-tocotrienol with PPARγ agonists reversed the growth inhibitory effects of γ-tocotrienol, whereas combined treatment of 1–4 μM  γ-tocotrienol with PPARγ antagonists synergistically inhibited MCF-7 and MDA-MB-231 cell growth. Combined treatment of γ-tocotrienol and PPARγ agonists caused an increase in transcription activity of PPARγ along with increased expression of PPARγ and RXR, and decrease in PPARγ coactivators, CBP p/300, CBP C-20, and SRC-1, in both breast cancer cell lines. In contrast, combined treatment of γ-tocotrienol with PPARγ antagonists resulted in a decrease in transcription activity of PPARγ, along with decreased expression of PPARγ and RXR, increase in PPARγ coactivators, and corresponding decrease in PI3K/Akt mitogenic signaling in these cells. These findings suggest that elevations in PPARγ are correlated with increased breast cancer growth and survival, and treatment that decreases PPARγ expression may provide benefit in the treatment of breast cancer.