Triple negative breast cancer initiating cell subsets differ in functional and molecular characteristics and in γ-secretase inhibitor drug responses

Authors

  • Diana J. Azzam,

    1. Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
    2. Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA
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  • Dekuang Zhao,

    1. Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
    2. Sheila and David Fuente Cancer Biology Program, Miami, FL, USA
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  • Jun Sun,

    1. Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
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  • Andy J. Minn,

    1. Department of Radiation Oncology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA
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  • Prathibha Ranganathan,

    1. Molecular Oncology, Department of Surgery, Sylvester Comprehensive Cancer Center, Miami, FL, USA
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  • Katherine Drews-Elger,

    1. Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
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  • Xiaoqing Han,

    1. Sheila and David Fuente Cancer Biology Program, Miami, FL, USA
    2. Molecular Oncology, Department of Surgery, Sylvester Comprehensive Cancer Center, Miami, FL, USA
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  • Manuel Picon-Ruiz,

    1. Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
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  • Candace A. Gilbert,

    1. Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
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  • Seth A. Wander,

    1. Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
    2. Sheila and David Fuente Cancer Biology Program, Miami, FL, USA
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  • Anthony J. Capobianco,

    1. Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA
    2. Molecular Oncology, Department of Surgery, Sylvester Comprehensive Cancer Center, Miami, FL, USA
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  • Dorraya El-Ashry,

    1. Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
    2. Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
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  • Joyce M. Slingerland

    Corresponding author
    1. Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
    2. Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA
    3. Sheila and David Fuente Cancer Biology Program, Miami, FL, USA
    4. Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
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Abstract

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.

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