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

Toni Celià-Terrassa, Daniel D. Liu, Abrar Choudhury, Xiang Hang, Yong Wei, Jose Zamalloa, Raymundo Alfaro-Aco, Rumela Chakrabarti, Yi Zhou Jiang, Bong Ihn Koh, Heath A. Smith, Christina Decoste, Jun Jing Li, Zhi Ming Shao, Yibin Kang

Research output: Contribution to journalArticle

43 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)711-723
Number of pages13
JournalNature cell biology
Volume19
Issue number6
DOIs
StatePublished - May 31 2017

All Science Journal Classification (ASJC) codes

  • Cell Biology

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    Celià-Terrassa, T., Liu, D. D., Choudhury, A., Hang, X., Wei, Y., Zamalloa, J., Alfaro-Aco, R., Chakrabarti, R., Jiang, Y. Z., Koh, B. I., Smith, H. A., Decoste, C., Li, J. J., Shao, Z. M., & Kang, Y. (2017). Normal and cancerous mammary stem cells evade interferon-induced constraint through the MIR-199a-LCOR axis. Nature cell biology, 19(6), 711-723. https://doi.org/10.1038/ncb3533