title: The shaping and functional consequences of the microRNA landscape in breast cancer.
abstract: 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.
authors: Cancer Research UK Cambridge Institute and Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors: Heidi
authors: H
authors: Dvinge
authors: Anna
authors: A
authors: Git
authors: Stefan
authors: S
authors: Gräf
authors: Mali
authors: M
authors: Salmon-Divon
authors: Christina
authors: C
authors: Curtis
authors: Andrea
authors: A
authors: Sottoriva
authors: Yongjun
authors: Y
authors: Zhao
authors: Martin
authors: M
authors: Hirst
authors: Javier
authors: J
authors: Armisen
authors: Eric A
authors: EA
authors: Miska
authors: Suet-Feung
authors: SF
authors: Chin
authors: Elena
authors: E
authors: Provenzano
authors: Gulisa
authors: G
authors: Turashvili
authors: Andrew
authors: A
authors: Green
authors: Ian
authors: I
authors: Ellis
authors: Sam
authors: S
authors: Aparicio
authors: Carlos
authors: C
authors: Caldas
mesh_terms: D000465:Algorithms; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D012334:RNA, Neoplasm
references: J Exp Med. 2011 Dec 19;208(13):2717-31
references: 22124110
references: Breast Cancer Res. 2008;10(3):R54
references: 18588681
references: Mol Biol Cell. 2005 Mar;16(3):1131-41
references: 15635089
references: Inflammation. 2012 Aug;35(4):1525-9
references: 22535496
references: Nat Rev Genet. 2010 Sep;11(9):597-610
references: 20661255
references: Biochim Biophys Acta. 2009 Jun;1792(6):497-505
references: 19268705
references: Genome Biol. 2007;8(10):R214
references: 17922911
references: Cell Cycle. 2010 Jun 1;9(11):2124-9
references: 20505365
references: Int J Biochem Cell Biol. 2010 Aug;42(8):1348-54
references: 20227518
references: Nature. 2012 Apr 18;486(7403):346-52
references: 22522925
references: Nature. 2012 Oct 4;490(7418):61-70
references: 23000897
references: Mol Oncol. 2010 Jun;4(3):230-41
references: 20537965
references: Nature. 2000 Aug 17;406(6797):747-52
references: 10963602
references: Cancer Res. 2011 Sep 1;71(17):5635-45
references: 21737487
references: Biochem Biophys Res Commun. 2009 Mar 13;380(3):437-41
references: 19284987
references: PLoS One. 2012;7(5):e36170
references: 22623953
references: Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):E2110-6
references: 22753494
references: Cell. 2011 Jun 10;145(6):926-40
references: 21663795
references: Genome Res. 2004 Sep;14(9):1741-8
references: 15310658
references: Cancer Res. 2011 Jul 1;71(13):4443-53
references: 21586611
references: FEBS J. 2012 Jul;279(13):2393-8
references: 22540680
references: PLoS One. 2011;6(5):e20341
references: 21647377
references: PLoS One. 2011 Feb 22;6(2):e16915
references: 21364938
references: Int J Oncol. 2009 Jan;34(1):231-42
references: 19082494
references: PLoS Biol. 2004 Apr;2(4):E108
references: 15094809
references: Nat Biotechnol. 2009 Sep;27(9):829-39
references: 19741643
references: Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15732-7
references: 19706389
references: Cancer Inform. 2012;11:61-75
references: 22570537
references: Int J Biochem Cell Biol. 2012 Sep;44(9):1465-72
references: 22642900
references: Genome Biol. 2007;8(8):R157
references: 17683518