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

TitleNormal and cancerous mammary stem cells evade interferon-induced constraint through the miR-199a-LCOR axis.
Publication TypeJournal Article
Year of Publication2017
AuthorsCelià-Terrassa, T, Liu, DD, Choudhury, A, Hang, X, Wei, Y, Zamalloa, J, Alfaro-Aco, R, Chakrabarti, R, Jiang, Y-Z, Koh, BIhn, Smith, HA, DeCoste, C, Li, J-J, Shao, Z-M, Kang, Y
JournalNat Cell Biol
Date Published2017 Jun
KeywordsAnimals, Breast Neoplasms, Cell Differentiation, Cell Movement, Cell Proliferation, Cell Self Renewal, Cell Transformation, Neoplastic, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, HEK293 Cells, HeLa Cells, Humans, Interferons, Mammary Glands, Animal, Mammary Glands, Human, MCF-7 Cells, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs, Neoplasm Metastasis, Neoplastic Stem Cells, Phenotype, Repressor Proteins, Signal Transduction, Transcription Factors, Transfection, Tumor Microenvironment

<p>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.</p>

Alternate JournalNat Cell Biol
PubMed ID28530657
PubMed Central IDPMC5481166
Grant ListP30 CA072720 / CA / NCI NIH HHS / United States
R01 CA141062 / CA / NCI NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States