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

Diana J. Azzam, Dekuang Zhao, Jun Sun, Andy J. Minn, Prathibha Ranganathan, Katherine Drews-Elger, Xiaoqing Han, Manuel Picon-Ruiz, Candace A. Gilbert, Seth A. Wander, Anthony J Capobianco, Dorraya El-Ashry, Joyce M Slingerland

Research output: Contribution to journalArticle

41 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1502-1522
Number of pages21
JournalEMBO Molecular Medicine
Volume5
Issue number10
DOIs
StatePublished - Oct 1 2013

Fingerprint

Triple Negative Breast Neoplasms
Amyloid Precursor Protein Secretases
Neoplastic Stem Cells
Pharmaceutical Preparations
Breast Neoplasms
Stem Cells
Heterografts
Population
Genes
Neoplasms

Keywords

  • Breast cancer stem cells
  • GSI
  • Metastasis
  • Notch1
  • Sox2

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Triple negative breast cancer initiating cell subsets differ in functional and molecular characteristics and in γ-secretase inhibitor drug responses. / Azzam, Diana J.; Zhao, Dekuang; Sun, Jun; Minn, Andy J.; Ranganathan, Prathibha; Drews-Elger, Katherine; Han, Xiaoqing; Picon-Ruiz, Manuel; Gilbert, Candace A.; Wander, Seth A.; Capobianco, Anthony J; El-Ashry, Dorraya; Slingerland, Joyce M.

In: EMBO Molecular Medicine, Vol. 5, No. 10, 01.10.2013, p. 1502-1522.

Research output: Contribution to journalArticle

Azzam, DJ, Zhao, D, Sun, J, Minn, AJ, Ranganathan, P, Drews-Elger, K, Han, X, Picon-Ruiz, M, Gilbert, CA, Wander, SA, Capobianco, AJ, El-Ashry, D & Slingerland, JM 2013, 'Triple negative breast cancer initiating cell subsets differ in functional and molecular characteristics and in γ-secretase inhibitor drug responses', EMBO Molecular Medicine, vol. 5, no. 10, pp. 1502-1522. https://doi.org/10.1002/emmm.201302558
Azzam, Diana J. ; Zhao, Dekuang ; Sun, Jun ; Minn, Andy J. ; Ranganathan, Prathibha ; Drews-Elger, Katherine ; Han, Xiaoqing ; Picon-Ruiz, Manuel ; Gilbert, Candace A. ; Wander, Seth A. ; Capobianco, Anthony J ; El-Ashry, Dorraya ; Slingerland, Joyce M. / Triple negative breast cancer initiating cell subsets differ in functional and molecular characteristics and in γ-secretase inhibitor drug responses. In: EMBO Molecular Medicine. 2013 ; Vol. 5, No. 10. pp. 1502-1522.
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