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Stem Cell Reports. 2014 Apr 24;2(5):633-47. doi: 10.1016/j.stemcr.2014.03.008. eCollection 2014 May 6.

Cell-state transitions regulated by SLUG are critical for tissue regeneration and tumor initiation.

Author information

1
Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA ; Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA.
2
Translational Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona 08035, Spain.
3
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge MA, 02142, USA.
4
Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
5
Department of Molecular Carcinogenesis, Science Park - Research Division, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
6
Department of Genetics and Pathology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27514, USA.
7
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge MA, 02142, USA ; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Abstract

Perturbations in stem cell activity and differentiation can lead to developmental defects and cancer. We use an approach involving a quantitative model of cell-state transitions in vitro to gain insights into how SLUG/SNAI2, a key developmental transcription factor, modulates mammary epithelial stem cell activity and differentiation in vivo. In the absence of SLUG, stem cells fail to transition into basal progenitor cells, while existing basal progenitor cells undergo luminal differentiation; together, these changes result in abnormal mammary architecture and defects in tissue function. Furthermore, we show that in the absence of SLUG, mammary stem cell activity necessary for tissue regeneration and cancer initiation is lost. Mechanistically, SLUG regulates differentiation and cellular plasticity by recruiting the chromatin modifier lysine-specific demethylase 1 (LSD1) to promoters of lineage-specific genes to repress transcription. Together, these results demonstrate that SLUG plays a dual role in repressing luminal epithelial differentiation while unlocking stem cell transitions necessary for tumorigenesis.

PMID:
24936451
PMCID:
PMC4050485
DOI:
10.1016/j.stemcr.2014.03.008
[Indexed for MEDLINE]
Free PMC Article

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