**Acknowledgements**

cell growth after a 4-day culture period. Furthermore, canonical Wnt and Hedgehog signaling are highly expressed in these triple negative breast cancer cells, and γ-tocotrienol growth inhibitory effects are associated with a reduction in Wnt and Hedgehog signaling and regulatory proteins. Since γ-tocotrienol also induces a reversal of EMT in these cells and canonical Wnt and Hedgehog signaling pathways are involved in promoting EMT, it can be concluded that γ-tocotrienol inhibition of EMT is mediated by a corresponding reduction in canonical Wnt and Hedgehog signaling in malignant MDA-MB-231 human breast cancer cells. This hypothesis is further evidenced by the finding that γ-tocotrienol inhibition of Wnt and Hedgehog signaling and reversal of EMT is associated with a significant decrease in

Metastasis is still the primary cause for the mortality (90%) in cancer patients with cancer. While a great deal of progress has been recently achieved in the further understanding of the molecular and cellular mechanisms involved in the metastatic process, these mechanisms are not completing understood and clinical therapies for the management and treatment of metastatic cancer remains insufficient. Expanding knowledge in gene expression, cellular behavior, and biological events of cancer cells will provide important and novel insights for the treatment of metastatic breast cancer. New biomarkers in areas, such as EMT will provide innovative chances in predictive methods of the metastatic potential of a primary tumor and a novel target for therapy. Experimental results summarized in **Figure 5** indicates some of the key targets in the treatment of EMT and metastasis and the possible role of γ-tocotrienol in

In summary, experimental evidence demonstrates that γ-tocotrienol reversal of EMT results, at least in part, through the inhibition of canonical Wnt and Hedgehog signaling. These findings also suggest that supplemental treatment with γ-tocotrienol may be effective in providing significant benefit in the prevention and treatment of metastatic breast

**Figure 5.** Schematic representation of γ-tocotrienol effects on the canonical Wnt and Hedgehog pathways and EMT. γ-Tocotrienol inhibits Wnt signaling by decreasing the expression of Wnt3a ligand, FZD7/LRP6 complex activation, DVL2 and cyclin D1 and a corresponding increase in Naked 1 level. Additionally, γ-tocotrienol inhibits Hedgehog signaling by decreasing the expression of Shh ligand, PTCH2, Smo, GSK3β, and Gli1 associated with a corresponding increase in SUFU levels. Several other cytosolic and nuclear proteins were minimized which can ultimately lead to a

migration, invasion and stemness of these cells [12].

94 Vitamin E in Health and Disease

the prevention and treatment of these processes.

suppression in gene expression associated with EMT.

cancer.

The work was performed in College of Pharmacy, University of Louisiana at Monroe, Monroe, LA. This work was supported by grants from First Tech International Ltd. (Hong Kong) and the Louisiana Cancer Foundation. The authors thank the First Tech International Ltd. for generously providing γ-tocotrienol for use in these studies. The authors also thank Dr. Karen P. Briski for her generous technical assistance and use of the laser confocal microscope.
