TY - JOUR
T1 - The shaping and functional consequences of the microRNA landscape in breast cancer
AU - Dvinge, Heidi
AU - Git, Anna
AU - Gräf, Stefan
AU - Salmon-Divon, Mali
AU - Curtis, Christina
AU - Sottoriva, Andrea
AU - Zhao, Yongjun
AU - Hirst, Martin
AU - Armisen, Javier
AU - Miska, Eric A.
AU - Chin, Suet Feung
AU - Provenzano, Elena
AU - Turashvili, Gulisa
AU - Green, Andrew
AU - Ellis, Ian
AU - Aparicio, Sam
AU - Caldas, Carlos
N1 - Funding Information:
Acknowledgements The study was funded by Cancer Research UK and the British Columbia Cancer Foundation. The authors also acknowledge the support of the University of Cambridge, Hutchinson Whampoa, the NIHR Cambridge Biomedical Research Centre, and the Cambridge Experimental Cancer Medicine Centre. We thank S.McGuire for help insamplemanagement;S.Fulmer-SmentekandT.Hillfor helpwith array design; L. Goldstein for initial processing of sequencing data; O. Rueda for statistical advice; and O. Rueda, J. Carroll and R. Ali for reading of the manuscript. We areverygratefultothepatients whodonatedtissueandassociatedpseudo-anonymized clinical data.
PY - 2013/5/16
Y1 - 2013/5/16
N2 - MicroRNAs (miRNAs) show differential expression across breast cancer subtypes, and have both oncogenic and tumour-suppressive roles. Here we report the miRNA expression profiles of 1, 302 breast tumours with matching detailed clinical annotation, long-term follow-up and genomic and messenger RNA expression data. This provides a comprehensive overview of the quantity, distribution and variation of the miRNA population and provides information on the extent to which genomic, transcriptional and post-transcriptional events contribute to miRNA expression architecture, suggesting an important role for post-transcriptional regulation. The key clinical parameters and cellular pathways related to the miRNA landscape are characterized, revealing context-dependent interactions, for example with regards to cell adhesion and Wnt signalling. Notably, only prognostic miRNA signatures derived from breast tumours devoid of somatic copy-number aberrations (CNA-devoid) are consistently prognostic across several other subtypes and can be validated in external cohorts. We then use a data-driven approach to seek the effects of miRNAs associated with differential co-expression of mRNAs, and find that miRNAs act as modulators of mRNA-mRNA interactions rather than as on-off molecular switches. We demonstrate such an important modulatory role for miRNAs in the biology of CNA-devoid breast cancers, a common subtype in which the immune response is prominent. These findings represent a new framework for studying the biology of miRNAs in human breast cancer.
AB - MicroRNAs (miRNAs) show differential expression across breast cancer subtypes, and have both oncogenic and tumour-suppressive roles. Here we report the miRNA expression profiles of 1, 302 breast tumours with matching detailed clinical annotation, long-term follow-up and genomic and messenger RNA expression data. This provides a comprehensive overview of the quantity, distribution and variation of the miRNA population and provides information on the extent to which genomic, transcriptional and post-transcriptional events contribute to miRNA expression architecture, suggesting an important role for post-transcriptional regulation. The key clinical parameters and cellular pathways related to the miRNA landscape are characterized, revealing context-dependent interactions, for example with regards to cell adhesion and Wnt signalling. Notably, only prognostic miRNA signatures derived from breast tumours devoid of somatic copy-number aberrations (CNA-devoid) are consistently prognostic across several other subtypes and can be validated in external cohorts. We then use a data-driven approach to seek the effects of miRNAs associated with differential co-expression of mRNAs, and find that miRNAs act as modulators of mRNA-mRNA interactions rather than as on-off molecular switches. We demonstrate such an important modulatory role for miRNAs in the biology of CNA-devoid breast cancers, a common subtype in which the immune response is prominent. These findings represent a new framework for studying the biology of miRNAs in human breast cancer.
UR - https://www.scopus.com/pages/publications/84878113369
U2 - 10.1038/nature12108
DO - 10.1038/nature12108
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C2 - 23644459
AN - SCOPUS:84878113369
SN - 0028-0836
VL - 497
SP - 378
EP - 382
JO - Nature
JF - Nature
IS - 7449
ER -