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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 1/2012

01-05-2012 | Preclinical Study

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

Authors: Alysha K. Croker, Alison L. Allan

Published in: Breast Cancer Research and Treatment | Issue 1/2012

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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 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 ALDHlowCD44− 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 ALDHhiCD44+ cells survived chemotherapy/radiotherapy relative to ALDHlowCD44− cells (P < 0.001). Glutathione-S-transferase 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.
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Metadata
Title
Inhibition of aldehyde dehydrogenase (ALDH) activity reduces chemotherapy and radiation resistance of stem-like ALDHhiCD44+ human breast cancer cells
Authors
Alysha K. Croker
Alison L. Allan
Publication date
01-05-2012
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2012
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-011-1692-y

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