| Treatment of tocotrienols in the highly malignant and metastatic +SA mouse mammary epithelial cells inhibits their growth and induces apoptosis in a time and a dose dependent manner. These results are observed at doses that have little or no effect on the proliferation and the viability of the normal mammary epithelial cells, and therefore, weigh therapeutic significance, and support the investigation of tocotrienols as potential adjuvant therapy in the prevention and the treatment of metastatic breast cancer. Studies were conducted to identify and investigate intracellular signal transduction mechanisms that are involved in the gamma-tocotrienol mediated anticancer effects in the +SA cells. Treatment with the growth inhibitory dose of gamma-tocotrienol resulted in a large decrease in the phosphorylated levels of Akt and suggested that the antiproliferative effects of gamma-tocotrienol in the +SA cells are associated with the suppression of the EGF (ErbB) induced PI3K/PDK-1/Akt mitogenic signaling. Studies that were conducted to determine the molecular target of inhibition by gamma-tocotrienol demonstrated no direct inhibitory effect of gamma-tocotrienol on any component along the PI3K/PDK-1/Akt signaling, suggesting that the inhibitory effects of gamma-tocotrienol were initiated upstream of the signaling cascade. Therefore, additional studies were conducted to determine the effects of gamma-tocotrienol on the ErbB receptor activation and results obtained therein demonstrated that although gamma-tocotrienol treatment had little or no effect on ErbB1 or ErbB2 receptor tyrosine phosphorylation, the same treatment caused a progressive decrease in the ErbB3 tyrosine phosphorylation, a prerequisite for the formation of the EGF receptor dimerization and activation of PI3K. Further, studies that were conducted to investigate the role played by the cell cycle regulators in the gamma-tocotrienol induced anticancer effects in the +SA cells demonstrated that both the gamma-tocotrienol mediated growth inhibition and the apoptosis of the +SA cells were associated with a large decrease in the levels and activity of cyclin D1 and cyclin-dependent kinase 4, which are the important regulators of the G1/S cell cycle checkpoint. Taken together, the studies conducted in the dissertation project have investigated and identified specific intracellular signal transduction mechanisms that underlie the gamma-tocotrienol mediated anticancer effects in the +SA mouse mammary epithelial cells. |
