Slug and Sox9 cooperatively determine the mammary stem cell state

Wenjun Guo, Zuzana Keckesova, Joana Liu Donaher, Tsukasa Shibue, Verena Tischler, Ferenc Reinhardt, Shalev Itzkovitz, Aurelia Noske, Ursina Zürrer-Härdi, George Bell, Wai Leong Tam, Sendurai A. Mani, Alexander Van Oudenaarden, Robert A. Weinberg

Research output: Contribution to journalArticlepeer-review

778 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1015-1028
Number of pages14
Issue number5
StatePublished - Mar 2 2012

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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