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

doi:10.1038/ncb3533

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

Nat Cell Biol. 2017 Jun;19(6):711-723. doi: 10.1038/ncb3533. Epub 2017 May 22.

Authors

Toni Celià-Terrassa¹, Daniel D Liu¹, Abrar Choudhury¹, Xiang Hang¹, Yong Wei¹, Jose Zamalloa^{1

2}, Raymundo Alfaro-Aco¹, Rumela Chakrabarti¹, Yi-Zhou Jiang^{3

4}, Bong Ihn Koh¹, Heath A Smith¹, Christina DeCoste¹, Jun-Jing Li^{3

4}, Zhi-Ming Shao^{3

4}, Yibin Kang¹

Affiliations

¹ Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
² Lewis-Sigler Institute, Princeton University, Princeton, New Jersey 08544, USA.
³ Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
⁴ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.

PMID: 28530657
PMCID: PMC5481166
DOI: 10.1038/ncb3533

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.

MeSH terms

Animals
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
Cell Differentiation
Cell Movement
Cell Proliferation*
Cell Self Renewal
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism*
Cell Transformation, Neoplastic / pathology
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
HEK293 Cells
HeLa Cells
Humans
Interferons / metabolism*
MCF-7 Cells
Mammary Glands, Animal / metabolism*
Mammary Glands, Animal / pathology
Mammary Glands, Human / metabolism*
Mammary Glands, Human / pathology
Mice, Inbred C57BL
Mice, Transgenic
MicroRNAs / genetics
MicroRNAs / metabolism*
Neoplasm Metastasis
Neoplastic Stem Cells / metabolism*
Neoplastic Stem Cells / pathology
Phenotype
Repressor Proteins / genetics
Repressor Proteins / metabolism*
Signal Transduction
Transcription Factors / genetics
Transcription Factors / metabolism*
Transfection
Tumor Microenvironment

Substances

LCOR protein, human
MicroRNAs
Mirn199 microRNA, mouse
Mlr2 protein, mouse
Repressor Proteins
Transcription Factors
mirn199 microRNA, human
Interferons

Abstract

MeSH terms

Substances

Grants and funding