Sensitivity of MCF-7 breast cancer cells to anticancer drugs is decreased by activation of the PI3K/PDK/Akt signal transduction pathway

Activation of signal transduction pathways regulating cell cycle progression and apoptosis have been associated with both breast cancer development and resistance to anticancer agents. A more thorough understanding of the mechanisms by which these pathways contribute to breast cancer development and resistance to anticancer agents will be helpful for improving breast cancer treatment. Effects of activation of the PI3K/PDK/Akt cascade on in vitro sensitivity of MCF-7 human breast cancer cells to anticancer agents was investigated. Ectopic expression of mutant forms of PTEN lacking lipid phosphatase activity decreased sensitivity of MCF-7 cells to doxorubicin. Ectopic expression of Bcl-2 in MCF-7 cells also conferred doxorubicin resistance. Additionally, stimulation of Akt1 activity decreased sensitivity of MCF-7 cells to 4-HT. These results indicate that activation of the PI3K/PDK/Akt cascade decreases sensitivity of MCF-7 cells to anticancer agents. Furthermore, induction of Bcl-2 expression may contribute to anticancer drug resistance mediated by the PI3K/PDK/Akt pathway. Mechanisms regulating activity of the PI3K/PDK/Akt cascade in FDC-P1 murine myeloid hematopoietic progenitor cells were also identified. Activation of MEK1 or conventional and novel PKCs induced phosphorylation of Akts, which demonstrates that conventional and novel PKCs activate the PI3K/PDK/Akt cascade in FDC-P1 cells. Furthermore, it is possible that MEK1 contributes to activation of this pathway by conventional and novel PKCs. These findings indicate that activation of the PI3K/PDK/Akt cascade may contribute to the cytokine independence of FDC-P1 cells that proliferate in the presence of PMA.