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

Phillips S1, Prat A2, Sedic M1, Proia T3, Wronski A1, Mazumdar S4, Skibinski A1, Shirley SH5, Perou CM6, Gill G4, Gupta PB7, Kuperwasser C1.
Source: Stem Cell Reports
Publication Date: (2014)
Issue: 2(5): 633-47
Research Area:
Basic Research
Cells used in publication:
Epithelial, mammary, human (HMEC)
Species: human
Tissue Origin: breast
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.