The synergistic effect between PDK1 inhibitor (OSU‐03012) and tamoxifen in ER positive and ER negative breast cancer

Abstract

Tamoxifen is being used widely in ER positive breast cancer patients for over a decade. Although it is believed that tamoxifen induces breast cancer cell lines’ growth arrest and apoptosis via estrogen receptor (ER) inhibition, the non-ER mediated mechanism has been reported in recent studies. On the other hand, the importance of phosphatidylinositol 3-kinase (PI3K)/PDK-1/Akt signaling cascade in breast cancer cell lines is well documented. Our study purpose is using the synergistic effect of Tamoxifen and the PDK1 inhibitor (OSU03012) to inhibit the cell proliferation on both ER positive and ER negative breast cancer cells through the cross talk between Akt inhibition and tamoxifen's non-ER target. Our results showed that tamoxifen induced apoptotic cell death by IC50 values of 13 μM and 15 μM in ER-positive MCF-7 cell line and ER-negative MDA-MB-231 breast cancer cells. Moreover, by adding 5 μM of OSU03012, the sensitivity to tamoxifen-induced apoptotic death was increased by around ten folds of magnitude. OSU03012 decreased the phospho-Akt level, which was transiently increased by tamoxifen and caused the down regulation of PDK-1/Akt machinery, such as GSK-3, and P27. The fluorescent microscope data also demonstrated that the FOXO3a nuclear translocation was increased with OSU03012 treatment. These findings indicate that tamoxifen and OSU03012 combination induces breast cancer apoptosis through the synergistic interactions between ER-independent and PI3K/PDK-1/Akt pathway. This study could be clinically exploited for ER-independent breast cancer therapy.