miR-155 Drives Telomere Fragility in Human Breast Cancer by Targeting TRF1

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 0 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 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. Cancer Res; 74(15); 4145-56. Ó2014 AACR.

TRF1 negotiates TTAGGG repeat-associated replication problems by recruiting the BLM helicase and the TPP1/POT1 repressor of ATR signaling

“…For instance, deletion of TRF1 in p53-deficient keratinocytes induces squamous cell carcinomas in mice (Martinez et al 2009), and the breast cancer-associated human miR-155 targets TRF1 and causes fragile telomeres (Dinami et al 2014). Furthermore, a mutation in RTEL1 that causes fragile telomeres accelerates tumorigenesis in p53-deficient mice, with the resulting tumor cells showing fragile telomeres and telomere fusions (Vannier et al 2013).…”

miR-204 regulates the biological behavior of breast cancer MCF-7 cells by directly targeting FOXA1

“…miRNAs play a vital role in breast cancer as they are reported to be involved in tumor progression, particularly in blocking apoptosis and promoting uncontrolled cell disruption (7). For example, miR-155, miR-373 and miR-520c have each been shown to be upregulated, and to act as oncogenic miRNAs in breast cancer (8)(9)(10), whereas miR-34, miR-200c and miR-205 have been shown to be downregulated and to act as tumor suppressors in breast cancer (11)(12)(13)(14). Li et al (15) demonstrated that the expression of miR-204 was expressed at markedly lower levels in breast cancer tissues than in adjacent normal breast tissues.…”

Noncoding RNAs: New Players in Cancers

“…The miR-290 cluster can infl uence telomere integrity and telomere-length homeostasis by targeting P130/RBL2 (retinoblastoma-like 2 protein), another member of the pRB family, and regulating RBL2-dependent Dnmt expression [ 122 ]. Upregulation of miR-155 drives telomere fragility in BrCa cells by decreasing TRF1 (shelterin component TERF1) levels and TRF1 abundance at telomeres, increasing the genomic instability linked to poor disease outcome [ 123 ]. Additionally, miR-34a induces senescence-like growth arrest by regulating the E2F pathway in human colon cancer cells [ 124 ].…”

“…As previously described, miRNA genes frequently map to genomic regions that are deleted, amplifi ed or translocated in cancer, such that variations of miRNA expression and miRNA-mediated gene regulation are implicated as key processes of oncogenesis and progression [ 69 , 135 ]. Apart from the abovementioned miR-15a/16-1 (chromosomal fragile site) and miR-17-92 clusters (amplifi ed gene locus) [ 73 ], miR-155-induced telomere fragility can augment genomic instability in BrCa [ 123 ].…”