Tumour-initiating cells (TICs) are responsible for metastatic dissemination and clinical relapse in a variety of cancers1,2 . Analogies between TICs and normal tissue stem cells have led to the proposal that activation of the normal stem-cell programwithin a tissue serves as the major mechanism for generating TICs3–7 . Supporting this notion, we and others previously established that the Slug epithelial-to-mesenchymal transition-inducing transcrip- tion factor (EMT-TF), a member of the Snail family, serves as a master regulator of the gland-reconstituting activity of normal mammary stem cells, and that forced expression of Slug in collab- oration with Sox9 in breast cancer cells can efficiently induce entrance into the TIC state8 . However, these earlier studies focused on xenograft models with cultured cell lines and involved ectopic expression of EMT-TFs, often at non-physiological levels. Using genetically engineered knock-in reportermouse lines, here we show thatnormalgland-reconstitutingmammary stemcells9–11 residingin the basal layer of the mammary epitheliumand breast TICs origin- ating in the luminal layer exploit the paralogous EMT-TFs Slug and Snail, respectively, which induce distinct EMT programs. Broadly, our findings suggest that the seemingly similar stem-cell programs operating in TICs and normal stemcells of the corresponding nor- mal tissue are likely to differ significantly in their details.
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