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

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.

• Authors: Sarah Phillips, Aleix Prat, Maja Sedic, Theresa Proia, Ania Wronski, Sohini Mazumdar, Adam Skibinski, Stephanie H Shirley, Charles M Perou, Grace Gill, Piyush B Gupta, Charlotte Kuperwasser
• Journal: Stem cell reports (Stem Cell Reports) Vol. 2 Issue 5 Pg. 633-47 (May 06 2014) ISSN: 2213-6711 [Print] United States
• PMID: 24936451 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Histones
• Proto-Oncogene Proteins c-myc
• RNA, Messenger
• SNAI1 protein, human
• SNAI2 protein, human
• Snai2 protein, mouse
• Snail Family Transcription Factors
• Transcription Factors

Topics

• Animals
• Cell Differentiation
• Cell Line
• Cell Lineage
• Cell Transformation, Neoplastic
• Disease-Free Survival
• Gene Expression Regulation
• Histones (metabolism)
• Humans
• Mammary Glands, Human (cytology)
• Mice
• Mice, Inbred NOD
• Mice, Knockout
• Mice, SCID
• Neoplasms (metabolism, mortality, pathology)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• RNA, Messenger (metabolism)
• Regeneration
• Snail Family Transcription Factors
• Stem Cell Transplantation
• Stem Cells (cytology, metabolism)
• Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Transplantation, Heterologous