miR-155 Drives Telomere Fragility in Human Breast Cancer by Targeting TRF1 Journal Articles uri icon

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  • Abstract Telomeres consist of DNA tandem repeats 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 3′UTR 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 miRNA-dependent 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. Cancer Res; 74(15); 4145–56. ©2014 AACR.


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

publication date

  • August 1, 2014