Slug and Sox9 Cooperatively Determine the Mammary Stem Cell State

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. [Display omitted] ► Slug and Sox9 suffice to convert differentiated mammary epithelial cells to stem cells ► Maintenance of naturally arising mammary stem cells (MaSCs) requires Slug and Sox9 ► These transcription factors activate autoregulatory genetic programs to induce MaSCs ► Slug and Sox9 promote breast cancer tumor-initiating and metastatic abilities Activation of two transcription factors, Slug and Sox9, is sufficient to convert differentiated mammary epithelial cells into stem cells and to promote metastasis in breast cancer cells.