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

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521 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1015-1028
Number of pages14
JournalCell
Volume148
Issue number5
DOIs
StatePublished - Mar 2 2012

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Guo, W., Keckesova, Z., Donaher, J. L., Shibue, T., Tischler, V., Reinhardt, F., Itzkovitz, S., Noske, A., Zürrer-Härdi, U., Bell, G., Tam, W. L., Mani, S. A., Van Oudenaarden, A., & Weinberg, R. A. (2012). Slug and Sox9 cooperatively determine the mammary stem cell state. Cell, 148(5), 1015-1028. https://doi.org/10.1016/j.cell.2012.02.008