Inhibition of aldehyde dehydrogenase (ALDH) activity reduces chemotherapy and radiation resistance of stem-like ALDHhiCD44+ human breast cancer cells

The majority of breast cancer deaths are because of ineffective treatment of metastatic disease. We previously identified a subpopulation of cells in human breast cancer cell lines that demonstrate high activity of aldehyde dehydrogenase (ALDH) and high expression of CD44. These ALDH hi CD44 + cells displayed enhanced metastatic behavior in vitro and in vivo relative to ALDH low CD44 − cells. The goal of this study was to test the hypothesis that ALDH hi CD44 + breast cancer cells are more resistant to standard cancer therapy, and that inhibiting ALDH activity through all- trans retinoic acid (ATRA) or the specific ALDH inhibitor diethylaminobenzaldehyde (DEAB) sensitizes these cells to treatment. ALDH hi CD44 + and ALDH low CD44 − populations were isolated from MDA-MB-231 and MDA-MB-468 cells lines and exposed to chemotherapy (doxorubicin/paclitaxel) or radiotherapy ± ATRA or DEAB. Cell populations were assessed for differences in survival, colony formation, and protein expression related to therapy resistance and differentiation. Significantly more ALDH hi CD44 + cells survived chemotherapy/radiotherapy relative to ALDH low CD44 − cells ( P