Mechanisms Mediating the Effects ofγ-Tocotrienol When Used in Combination with PPARγAgonists or Antagonists on MCF-7 and MDA-MB-231 Breast Cancer Cells

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