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

Nature
Xin YeRobert A Weinberg

Abstract

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 ...Continue Reading

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Datasets Mentioned

BETA
GSE2990
GSE3494
GSE4922
GSE6532
GSE7390
GSE12093
GSE5327
GSE9195
GSE16391
GSE21653

Methods Mentioned

BETA
fluorescence-activated cell sorting
transgenic
ChIP-seq
PCR
genotyping
FACS
flow cytometry
dissecting
immunoprecipitation
ChIP

Software Mentioned

GSEA
Extreme Limiting Dilution Analysis
Zen

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