Slug and Sox9 Cooperatively Determine the Mammary Stem Cell State

Cell. 2012 Mar 2;148(5):1015-28. doi: 10.1016/j.cell.2012.02.008.

Abstract

Regulatory networks orchestrated by key transcription factors (TFs) have been proposed to play a central role in the determination of stem cell states. However, the master transcriptional regulators of adult stem cells are poorly understood. We have identified two TFs, Slug and Sox9, that act cooperatively to determine the mammary stem cell (MaSC) state. Inhibition of either Slug or Sox9 blocks MaSC activity in primary mammary epithelial cells. Conversely, transient coexpression of exogenous Slug and Sox9 suffices to convert differentiated luminal cells into MaSCs with long-term mammary gland-reconstituting ability. Slug and Sox9 induce MaSCs by activating distinct autoregulatory gene expression programs. We also show that coexpression of Slug and Sox9 promotes the tumorigenic and metastasis-seeding abilities of human breast cancer cells and is associated with poor patient survival, providing direct evidence that human breast cancer stem cells are controlled by key regulators similar to those operating in normal murine MaSCs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism*
  • Cells, Cultured
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Mammary Glands, Human / cytology*
  • Mammary Glands, Human / metabolism
  • Mice
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism*
  • Snail Family Transcription Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • SNAI1 protein, human
  • SOX9 Transcription Factor
  • SOX9 protein, human
  • Snai2 protein, mouse
  • Snail Family Transcription Factors
  • Sox9 protein, mouse
  • Transcription Factors