Abstract P5-03-12: Targeting breast cancer stem cells using the autopahgy inhibitor N-Acetyl cysteine

Abstract

Abstract Introduction: One in eight women is diagnosed with breast cancer in the United States. The most aggressive form of breast cancer is the “triple negative breast cancer” (TNBCs), where there is a lack of expression of all three receptors, namely ER, PR and HER2 and a lack of targeted therapies lead to the highest relapse rate in breast cancer. This makes it imperative to identify and target the mechanism of relapse of this cancer. We have recently identified autophagy as a mechanism of tumor resistant cell survival in breast cancer. We have demonstrated an increase in autophagy in chemotherapy treated patients. Further, we have shown that addition of a stem cell inhibitor against NOTCH reduces autophagy and stem cells population. In order to eliminate these tumor resistant cells from surviving chemotherapy, we plan to target the cell survival pathway of autophagy using N-acetyl csyteine as a novel inhibitor. Materials and Methods: We treated three triple negative cell lines (SUM159, BT549 and MDA-MB231) with varying concentrations of N-acetyl cysteine and determined its impact on tumor initiating cells via mammosphere formation and FACS sorting of CD44hi/CD24low cells. N-acetyl cysteine affects mitochondrial metabolism so we tested its impact on mitochondrial DNA mass. Results: N-acetyl cysteine significantly decreased TIC population as evidenced by the remarkable reduction in mammosphere formation efficiency and levels of CD44hi/24low cells at 1 and 10uM in all three cell lines. In two cells lines we have demonstrated that there is a significant increase in mitochondrial mass upon treatment of NAC. Conclusion: We have currently determined that N-acetyl cysteine works via autophagy and eliminates tumor initiating cell population. We have also demonstrated that this involves changing the mitochondrial mass and overall changes in the metabolism of these cells. This novel interlink between mitochondrial metabolism and autophagy provided a new insight into the role of tumor initiating cells in breast cancer and possible new approaches to treat therapy resistance in triple negative breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-03-12.