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 journalArticle

493 Citations (Scopus)

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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Gastropoda
Stem cells
Breast
Stem Cells
Breast Neoplasms
Transcription Factors
Adult Stem Cells
Neoplastic Stem Cells
Human Mammary Glands
Gene expression
Epithelial Cells
Neoplasm Metastasis
Gene Expression
Cells
Survival

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., ... 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

Slug and Sox9 cooperatively determine the mammary stem cell state. / Guo, Wenjun; Keckesova, Zuzana; Donaher, Joana Liu; Shibue, Tsukasa; Tischler, Verena; Reinhardt, Ferenc; Itzkovitz, Shalev; Noske, Aurelia; Zürrer-Härdi, Ursina; Bell, George; Tam, Wai Leong; Mani, Sendurai A.; Van Oudenaarden, Alexander; Weinberg, Robert A.

In: Cell, Vol. 148, No. 5, 02.03.2012, p. 1015-1028.

Research output: Contribution to journalArticle

Guo, W, Keckesova, Z, Donaher, JL, Shibue, T, Tischler, V, Reinhardt, F, Itzkovitz, S, Noske, A, Zürrer-Härdi, U, Bell, G, Tam, WL, Mani, SA, Van Oudenaarden, A & Weinberg, RA 2012, 'Slug and Sox9 cooperatively determine the mammary stem cell state', Cell, vol. 148, no. 5, pp. 1015-1028. https://doi.org/10.1016/j.cell.2012.02.008
Guo W, Keckesova Z, Donaher JL, Shibue T, Tischler V, Reinhardt F et al. Slug and Sox9 cooperatively determine the mammary stem cell state. Cell. 2012 Mar 2;148(5):1015-1028. https://doi.org/10.1016/j.cell.2012.02.008
Guo, Wenjun ; Keckesova, Zuzana ; Donaher, Joana Liu ; Shibue, Tsukasa ; Tischler, Verena ; Reinhardt, Ferenc ; Itzkovitz, Shalev ; Noske, Aurelia ; Zürrer-Härdi, Ursina ; Bell, George ; Tam, Wai Leong ; Mani, Sendurai A. ; Van Oudenaarden, Alexander ; Weinberg, Robert A. / Slug and Sox9 cooperatively determine the mammary stem cell state. In: Cell. 2012 ; Vol. 148, No. 5. pp. 1015-1028.
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