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miR-155 drives telomere fragility in human breast cancer by targeting TRF1
- Source :
- Cancer research. 74(15)
- Publication Year :
- 2014
-
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.
- Subjects :
- Genome instability
Cancer Research
3' Untranslated Regions
Animals
Base Sequence
Breast Neoplasms
Cell Culture Techniques
Female
HCT116 Cells
HeLa Cells
Humans
MCF-7 Cells
MicroRNAs
Molecular Sequence Data
Sequence Homology, Nucleic Acid
Telomere
Telomeric Repeat Binding Protein 1
Transfection
Sequence Homology
Biology
TERF1
miR-155
Breast cancer
Telomere Homeostasis
breast cancer
medicine
miR-155, breast cancer, telomeres, shelterin
Nucleic Acid
medicine.disease
Shelterin
telomeres
Chromatin
Oncology
Cancer cell
Cancer research
shelterin
Subjects
Details
- ISSN :
- 15387445
- Volume :
- 74
- Issue :
- 15
- Database :
- OpenAIRE
- Journal :
- Cancer research
- Accession number :
- edsair.doi.dedup.....7d5ac706b072949814ce826bef7d5995