Targeting aberrant expression of Notch‐1 in ALDH+ cancer stem cells in breast cancer

• Published in: Molecular carcinogenesis Vol. 56; no. 3; pp. 1127 - 1136
• Main Authors: Pal, Deeksha, Kolluru, Venkatesh, Chandrasekaran, Balaji, Baby, Becca V., Aman, Masarath, Suman, Suman, Sirimulla, Suman, Sanders, Mary Ann, Alatassi, Houda, Ankem, Murali K., Damodaran, Chendil
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.03.2017
• Subjects: Aldehyde Dehydrogenase - metabolism; Animals; Benzofurans - administration & dosage; Benzofurans - pharmacology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer therapies; Cell Line, Tumor; Coumarins - administration & dosage; Coumarins - pharmacology; Enzymes; Epithelial-Mesenchymal Transition - drug effects; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Metastasis; Mice; Neoplasm Grading; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; prevention; Receptor, Notch1 - metabolism; Signal Transduction - drug effects; Stem cells; Up-Regulation - drug effects; Xenograft Model Antitumor Assays; stem cells; breast cancer; prevention
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.22579

We have previously reported that high aldehyde dehydrogenase (ALDH) enzyme activity in breast cancer cells results in breast cancer stem cell (BCSC) properties by upregualting Notch‐1 and epithelial mesenchymal markers. This results in chemoresistance in breast cancer. Here, we examined the functional and clinical significance of ALDH expression by measuring the ALDH levels in breast cancer tissues by immunohistochemistry. There was a significantly higher ALDH expression in higher grade breast cancer tumor tissues (Grade‐ II and III) versus normal breast tissues. Injection of BCSC (ALDH+ and CD44+/CD22−) cells resulted in aggressive tumor growth in athymic mice versus ALDH− cells. The ALDH+ and CD44+/CD22− tumors grow rapidly and are larger than ALDH− tumors which were slow growing and smaller. Molecularly, ALDH+ tumors expressed higher expression of Notch‐1 and EMT markers than ALDH− tumors. Oral administration of the naturally occurring Psoralidin (Pso, 25 mg/kg of body weight) significantly inhibited the growth in ALDH+ and ALDH− tumors as well. Psoralidin inhibited Notch‐1 mediated EMT activation in ALDH+ and ALDH− tumors‐this confirms our in vitro findings. Our results suggest that Notch‐1 could be an attractive target and inhibition of Notch‐1 by Psoralidin may prevent pathogenesis of breast cancer as well as metastasis. © 2016 Wiley Periodicals, Inc.