Distinct EMT programs control normal mammary stem cells and tumour-initiating cells.
Tumour-initiating cells (TICs) are responsible for metastatic dissemination and clinical relapse in a variety of cancers. Analogies between TICs and normal tissue stem cells have led to the proposal that activation of the normal stem-cell program within a tissue serves as the major mechanism for generating TICs. Supporting this notion, we and others previously established that the Slug epithelial-to-mesenchymal transition-inducing transcription 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 collaboration with Sox9 in breast cancer cells can efficiently induce entrance into the TIC state. 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 mammary stem cells 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 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.
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Xin
X
Ye
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.|Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.|Cancer Science Institute of Singapore, 14 Medical Drive, Singapore 117599, Singapore.
Wai Leong
WL
Tam
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Tsukasa
T
Shibue
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Yasemin
Y
Kaygusuz
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Ferenc
F
Reinhardt
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Elinor
E
Ng Eaton
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Ludwig Center for Molecular Oncology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Robert A
RA
Weinberg
D000818:Animals; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D008321:Mammary Glands, Animal / Q000166:cytology*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism
D055758:SOX9 Transcription Factor; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; C527933:Sox9 protein, mouse; D014157:Transcription Factors