• Major finding: Mammary stem cell formation is regulated by SLUG and SOX9.

  • Concept: SLUG and SOX9 activate distinct but cooperative genetic networks.

  • Impact: A master regulator program maintains the adult stem cell state.

Master transcription regulatory networks have been shown to play a role in the establishment of the embryonic stem cell (SC) state. However, the factors that control adult SC programs have not yet been defined. Guo and colleagues identified SLUG and SOX9 to be the key transcription factors that cooperatively regulate the mammary SC (MaSC) state. The authors first found enriched expression of SLUG, a transcription factor implicated in the epithelial–mesenchymal transition, in murine MaSCs. SOX9 was then identified in a screen for factors that acted cooperatively with SLUG to establish the MaSC state. Transient coexpression of SOX9 and SLUG in mammary epithelial cells was sufficient to induce the formation of self-renewing MaSCs capable of long-term mammary gland repopulation, and knockdown of either factor abrogated this activity. Using gene expression analyses, the authors confirmed that SLUG and SOX9 each activated a distinct genetic program that was required for MaSC formation and continued to maintain the MaSC state even after the expression of each factor was silenced. These factors also were shown to regulate human breast cancer SCs, as SLUG and SOX9 overexpression in nonmetastatic breast cancer cells converted them into metastasis-seeding cells. In addition, high expression levels of both SLUG and SOX9 were associated with poor outcome in patients with breast cancer. This study not only identifies a conserved and clinically relevant MaSC regulatory network but also provides insight into the genetic programs that potentially determine the SC state of other types of adult epithelial cells.

Guo W, Keckesova Z, Liu Donaher J, Shibue T, Tischler V, Reinhardt F, et al. Slug and Sox9 cooperatively determine the mammary stem cell state. Cell 2012;148:1015–28.

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