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 ALDHhiCD44? cells displayed enhanced metastatic behavior in vitro and in vivo relative to ALDHlowCD44- cells. The goal of this study was to test the hypothesis that ALDHhiCD44? 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. ALDHhiCD44? and ALDHlow 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 ALDHhi CD44? cells survived chemotherapy/radiotherapy relative to ALDHlowCD44- cells (P\0.001). Glutathione-Stransferase pi, p-glycoprotein, and/or CHK1 were overexpressed in ALDHhiCD44? populations compared with ALDHlowCD44- populations (P\0.05). Pre-treatment of cell populations with DEAB or ATRA had no effect on ALDHlowCD44- cells, but resulted in significant initial sensitization of ALDHhiCD44? cells to chemotherapy/ radiotherapy. However, only DEAB had a long-term effect, resulting in reduced colony formation (P\0.01). ATRA also significantly increased expression of CK8/18/19 in MDA-MB-468 ALDHhiCD44? cells compared with control (P\0.05). Our novel findings indicate that ALDHhiCD44? breast cancer cells contribute to both chemotherapy and radiation resistance and suggest a much broader role for ALDH in treatment response than previously reported.