Tumor initiation and progression are mainly driven by a small subset of stem cells- like cancer cells (CSCs), which represent <1 % of malignant breast tumors. Most importantly breast CSCs are highly resistant to radiation- and chemo-therapy. Such resistance could be attributed to the high expression of the enzyme, Aldehyde dehydrogenase I (ALDH1), which in recent years has been suggested to be a prognostic marker of breast cancer. However, the mechanism(s) of ALDH1's involvement in CSCs’ function and resistance to radiation/chemotherapy (oxidative stress) and its role in breast cancer progression are not known. Toxicity of most of the chemotherapeutic drugs is known to be via increased oxidative stress which generates lipid aldehydes such as 4-hydroxynonenal (HNE), a potent apoptotic agent. In CSCs the levels of ALDH1 are much higher than the normal breast cell as well as cancer cells. It is likely that the resistance of CSCs to chemotherapeutic drugs is due to increased levels of ALDH1 which is known to detoxify HNE generated by oxidative stress caused by chemotherapeutic drugs. Increased HNE could kill the cells by causing increased apoptosis. To test this hypothesis we inhibited ALDH1 in the tumoregenic human breast cancer cells, MDA-MB-468, by diethylaminobenzaldehyde (DEAB) and measured HNE-induced toxicity by evaluating the levels of protein-HNE adducts which, as previously demonstrated by us, increase in oxidation-induced apoptosis. ALDH1hi/CD44+ and ALDH1low/ CD44+ cells were sorted by flow cytometry using ALDEFLUO-FITC & mouse anti-Human CD44-APC. The DEAB-treated cells when subjected to oxidative stress by H2O2, showed increased formation of protein -HNE adducts with a concomitant increase in apoptosis and decrease in cell viability. Furthermore, our results also displayed increased activation of the transcription factor, NF-kB which could be responsible for up-regulating the death genes leading to apoptosis. In addition, four specimens of human malignant breast cancer tissues and two of benign breast tumors were analyzed by double immunostaining. Compared to benign tumors, elevated levels of ALDH1 and CSC-like cells (high ALDH1/high CD44/lowCD24) were observed in the breast cancer tissues. Furthermore, levels of ALDH1 in these specimens appeared to be proportional to the grade of cancer. Our results thus suggest that disrupting ALDH1-mediated HNE detoxification in CSCs could be a novel preventive approach against breast cancer progression and metastasis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 54.