Normal and cancerous mammary stem cells evade interferon-induced constraint through the miR-199a-LCOR axis

Nature Cell Biology
Toni Celià-TerrassaYibin Kang

Abstract

Tumour-initiating cells, or cancer stem cells (CSCs), possess stem-cell-like properties observed in normal adult tissue stem cells. Normal and cancerous stem cells may therefore share regulatory mechanisms for maintaining self-renewing capacity and resisting differentiation elicited by cell-intrinsic or microenvironmental cues. Here, we show that miR-199a promotes stem cell properties in mammary stem cells and breast CSCs by directly repressing nuclear receptor corepressor LCOR, which primes interferon (IFN) responses. Elevated miR-199a expression in stem-cell-enriched populations protects normal and malignant stem-like cells from differentiation and senescence induced by IFNs that are produced by epithelial and immune cells in the mammary gland. Importantly, the miR-199a-LCOR-IFN axis is activated in poorly differentiated ER- breast tumours, functionally promotes tumour initiation and metastasis, and is associated with poor clinical outcome. Our study therefore reveals a common mechanism shared by normal and malignant stem cells to protect them from suppressive immune cytokine signalling.

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Datasets Mentioned

BETA
GSE52262
GSE85808
GSE76250
GSE22220

Methods Mentioned

BETA
fluorescence-activated cell sorting
xenografts
flow cytometry
ELISA
dissection
Biosample
PCR
transfection
FACS
gene knock-down

Software Mentioned

KM plotter
Agilent Feature Extraction
ELDA ( Extreme limiting dilution analysis )
Excel
R voom package
ELDA
GSEA
GraphPad Prism6
GeneSpring GX
limma

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