Triple negative breast cancer initiating cell subsets differ in functional and molecular characteristics and in γ-secretase inhibitor drug responses
Article first published online: 27 AUG 2013
Copyright © 2013 EMBO Molecular Medicine
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 5, Issue 10, pages 1502–1522, October 2013
How to Cite
Azzam, D. J., Zhao, D., Sun, J., Minn, A. J., Ranganathan, P., Drews-Elger, K., Han, X., Picon-Ruiz, M., Gilbert, C. A., Wander, S. A., Capobianco, A. J., El-Ashry, D. and Slingerland, J. M. (2013), Triple negative breast cancer initiating cell subsets differ in functional and molecular characteristics and in γ-secretase inhibitor drug responses. EMBO Mol Med, 5: 1502–1522. doi: 10.1002/emmm.201302558
- Issue published online: 2 OCT 2013
- Article first published online: 27 AUG 2013
- Manuscript Accepted: 16 JUL 2013
- Manuscript Revised: 15 JUL 2013
- Manuscript Received: 25 JAN 2013
- NIH-NCI. Grant Number: T32-CA119929-04
- breast cancer stem cells;
Increasing evidence suggests that stem-like cells mediate cancer therapy resistance and metastasis. Breast tumour-initiating stem cells (T-ISC) are known to be enriched in CD44+CD24neg/low cells. Here, we identify two T-ISC subsets within this population in triple negative breast cancer (TNBC) lines and dissociated primary breast cancer cultures: CD44+CD24low+ subpopulation generates CD44+CD24neg progeny with reduced sphere formation and tumourigenicity. CD44+CD24low+ populations contain subsets of ALDH1+ and ESA+ cells, yield more frequent spheres and/or T-ISC in limiting dilution assays, preferentially express metastatic gene signatures and show greater motility, invasion and, in the MDA-MB-231 model, metastatic potential. CD44+CD24low+ but not CD44+CD24neg express activated Notch1 intracellular domain (N1-ICD) and Notch target genes. We show N1-ICD transactivates SOX2 to increase sphere formation, ALDH1+ and CD44+CD24low+cells. Gamma secretase inhibitors (GSI) reduced sphere formation and xenograft growth from CD44+CD24low+ cells, but CD44+CD24neg were resistant. While GSI hold promise for targeting T-ISC, stem cell heterogeneity as observed herein, could limit GSI efficacy. These data suggest a breast T-ISC hierarchy in which distinct pathways drive developmentally related subpopulations with different anti-cancer drug responsiveness.