title: 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'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.
authors.affiliation: Telomeres in Cancer and Aging Unit, Dipartimento di Scienze della Vita, SDBM School of Molecular Biomedicine (SDBM), Università degli Studi di Trieste, Trieste; Telomeres in Cancer and Aging Unit.
authors.forename: Roberto
authors.initials: R
authors.lastname: Dinami
authors.affiliation: Department of Pathology, Regina Elena National Cancer Institute, Rome;
authors.forename: Cristiana
authors.initials: C
authors.lastname: Ercolani
authors.affiliation: Telomeres in Cancer and Aging Unit, Dipartimento di Scienze della Vita, SDBM School of Molecular Biomedicine (SDBM), Università degli Studi di Trieste, Trieste; Telomeres in Cancer and Aging Unit.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Petti
authors.affiliation: Bioinformatics and Functional Genomics Unit, and.
authors.forename: Silvano
authors.initials: S
authors.lastname: Piazza
authors.affiliation: Bioinformatics and Functional Genomics Unit, and.
authors.forename: Yari
authors.initials: Y
authors.lastname: Ciani
authors.affiliation: Telomeres in Cancer and Aging Unit.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Sestito
authors.affiliation: Translational Oncogenomics Unit, and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sacconi
authors.affiliation: Translational Oncogenomics Unit, and.
authors.forename: Francesca
authors.initials: F
authors.lastname: Biagioni
authors.affiliation: Division of Gene Regulation, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Carlos
authors.initials: C
authors.lastname: le Sage
authors.affiliation: Division of Gene Regulation, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Reuven
authors.initials: R
authors.lastname: Agami
authors.affiliation: Epigenetics Unit, Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB); Dipartimento di Scienze Mediche e Biologiche, Universita degli Studi di Udine, Udine, Italy; and.
authors.forename: Roberta
authors.initials: R
authors.lastname: Benetti
authors.affiliation: Department of Pathology, Regina Elena National Cancer Institute, Rome;
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.affiliation: Bioinformatics and Functional Genomics Unit, and Dipartimento di Scienze Mediche e Biologiche, Universita degli Studi di Udine, Udine, Italy; and.
authors.forename: Claudio
authors.initials: C
authors.lastname: Schneider
authors.affiliation: Translational Oncogenomics Unit, and.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Blandino
authors.affiliation: Telomeres in Cancer and Aging Unit, Telomeres in Cancer and Aging Unit, stefan.schoeftner@lncib.it.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schoeftner
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D018929:Cell Culture Techniques; D005260:Female; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D012689:Sequence Homology, Nucleic Acid; D016615:Telomere / Q000235:genetics* / Q000378:metabolism; D035321:Telomeric Repeat Binding Protein 1 / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D035321:Telomeric Repeat Binding Protein 1