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.
期刊论文详细信息
EMBO Molecular Medicine | |
Triple negative breast cancer initiating cell subsets differ in functional and molecular characteristics and in γ‐secretase inhibitor drug responses | |
Diana J. Azzam5  Dekuang Zhao5  Jun Sun5  Andy J. Minn4  Prathibha Ranganathan2  Katherine Drews-Elger5  Xiaoqing Han3  Manuel Picon-Ruiz5  Candace A. Gilbert5  Seth A. Wander5  Anthony J. Capobianco1  Dorraya El-Ashry5  | |
[1] Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA;Molecular Oncology, Department of Surgery, Sylvester Comprehensive Cancer Center, Miami, FL, USA;Sheila and David Fuente Cancer Biology Program, Miami, FL, USA;Department of Radiation Oncology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA;Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA | |
关键词: breast cancer stem cells; GSI; metastasis; Notch1; Sox2; | |
DOI : 10.1002/emmm.201302558 | |
来源: Wiley | |
【 摘 要 】
Abstract
【 授权许可】
CC BY
Copyright © 2013 EMBO Molecular Medicine
Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
【 预 览 】
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