Distinct EMT programs control normal mammary stem cells and tumour-initiating cells

Abstract

Tumour-initiating cells (TICs) are responsible for metastatic dissemination and clinical relapse in a variety of cancers ^{1, 2} . Analogies between TICs and normal tissue stem cells have led to the notion that activation of the normal stem-cell program within a tissue serves as the major mechanism for generating TICs ^{3- 7} . Supporting this notion, we and others previously established that the Slug EMT-TF (EMT-inducing transcription factor), a member of the Snail family, is a master regulator of the gland-reconstituting activity of normal mammary stem cells (MaSCs), and that forced expression of Slug in collaboration with Sox9 in breast cancer cells can efficiently induce entrance into the TIC state ⁸ . 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 reporter mouse lines, here we show that normal gland-reconstituting MaSCs ^{9- 11} residing in the basal layer of the mammary epithelium and breast TICs originating in the luminal layer exploit the paralogous EMT-TFs Slug and Snail respectively, which induce in turn distinct EMT programs. Broadly, our findings suggest that the seemingly similar stem-cell programs operating in TICs and normal stem cells of the corresponding normal tissue are likely to differ significantly in their details.