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Breast Cancer Res Treat. 2012 May;133(1):75-87. doi: 10.1007/s10549-011-1692-y. Epub 2011 Aug 5.

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

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1
Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.

Abstract

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 < 0.001). Glutathione-S-transferase pi, p-glycoprotein, and/or CHK1 were overexpressed in ALDH(hi)CD44(+) populations compared with ALDH(low)CD44(-) populations (P < 0.05). Pre-treatment of cell populations with DEAB or ATRA had no effect on ALDH(low)CD44(-) cells, but resulted in significant initial sensitization of ALDH(hi)CD44(+) 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 ALDH(hi)CD44(+) cells compared with control (P < 0.05). Our novel findings indicate that ALDH(hi)CD44(+) breast cancer cells contribute to both chemotherapy and radiation resistance and suggest a much broader role for ALDH in treatment response than previously reported.

PMID:
21818590
DOI:
10.1007/s10549-011-1692-y
[Indexed for MEDLINE]

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