miR-155 drives telomere fragility in human breast cancer by targeting TRF1

Roberto Dinami, Cristiana Ercolani, Eleonora Petti, Silvano Piazza, Yari Ciani, Rosanna Sestito, Andrea Sacconi, Francesca Biagioni, Carlos Le Sage, Reuven Agami, Roberta Benetti, Marcella Mottolese, Claudio Schneider, Giovanni Blandino, Stefan Schoeftner

Research output: Contribution to journalArticlepeer-review

Abstract

Telomeres consist of DNA tandemrepeats that recruit the multiprotein complex shelterin to build a chromatin structure that protects chromosome ends. Although cancer formation is linked to alterations in telomere homeostasis, there is little understanding of how shelterin function is limited in cancer cells. Using a small-scale screening approach, we identified miR-155 as a key regulator in breast cancer cell expression of the shelterin component TERF1 (TRF1). miR-155 targeted a conserved sequence motif in the 30UTR of TRF1, resulting in its translational repression. miR-155 was upregulated commonly in breast cancer specimens, as associated with reduced TRF1 protein expression, metastasis-free survival, and relapse-free survival in estrogen receptor-positive cases. Modulating miR-155 expression in cells altered TRF1 levels and TRF1 abundance at telomeres. Compromising TRF1 expression by elevating miR-155 increased telomere fragility and altered the structure of metaphase chromosomes. In contrast, reducing miR-155 levels improved telomere function and genomic stability. These results implied that miR-155 upregulation antagonizes telomere integrity in breast cancer cells, increasing genomic instability linked to poor clinical outcome in estrogen receptor-positive disease. Our work argued that miRNAdependent regulation of shelterin function has a clinically significant impact on telomere function, suggesting the existence of "telo-miRNAs" that have an impact on cancer and aging.

Original languageEnglish
Pages (from-to)4145-4156
Number of pages12
JournalCancer Research
Volume74
Issue number15
DOIs
Publication statusPublished - Aug 1 2014

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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