Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The shaping and functional consequences of the microRNA landscape in breast cancer



MicroRNAs (miRNAs) show differential expression across breast cancer subtypes, and have both oncogenic and tumour-suppressive roles1,2,3,4,5,6. 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 data7. 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 approach8 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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Factors shaping the miRNA landscape across the breast cancer genome.
Figure 2: Cellular processes connected to the miRNA landscape.
Figure 3: miRNAs have an increased prognostic value in the genomically stable iClust4.
Figure 4: miRNAs have a significant modulatory role in iClust4.

Accession codes

Data deposits

The raw non-coding RNA microarray data is available through the European Genome–Phenome Archive (, which is hosted by the EBI, under accession number GAS00000000122.


  1. Le Quesne, J. & Caldas, C. Micro-RNAs and breast cancer. Mol. Oncol. 4, 230–241 (2010)

    CAS  Article  Google Scholar 

  2. Buffa, F. M. et al. microRNA-associated progression pathways and potential therapeutic targets identified by integrated mRNA and microRNA expression profiling in breast cancer. Cancer Res. 71, 5635–5645 (2011)

    CAS  Article  Google Scholar 

  3. Enerly, E. et al. miRNA-mRNA integrated analysis reveals roles for miRNAs in primary breast tumors. PLoS ONE 6, e16915 (2011)

    CAS  ADS  Article  Google Scholar 

  4. Farazi, T. A. et al. MicroRNA sequence and expression analysis in breast tumors by deep sequencing. Cancer Res. 71, 4443–4453 (2011)

    CAS  Article  Google Scholar 

  5. Lyng, M. B. et al. Global microRNA expression profiling of high-risk ER+ breast cancers from patients receiving adjuvant tamoxifen mono-therapy: a DBCG study. PLoS ONE 7, e36170 (2012)

    CAS  ADS  Article  Google Scholar 

  6. The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012)

  7. Curtis, C. et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486, 346–352 (2012)

    CAS  Article  Google Scholar 

  8. Wang, K. et al. Genome-wide identification of post-translational modulators of transcription factor activity in human B cells. Nature Biotechnol. 27, 829–837 (2009)

    CAS  Article  Google Scholar 

  9. Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000)

    CAS  ADS  Article  Google Scholar 

  10. Olive, V., Jiang, I. & He, L. mir-17–92, a cluster of miRNAs in the midst of the cancer network. Int. J. Biochem. Cell Biol. 42, 1348–1354 (2010)

    CAS  Article  Google Scholar 

  11. Valastyan, S. & Weinberg, R. A. miR-31: a crucial overseer of tumor metastasis and other emerging roles. Cell Cycle 9, 2124–2129 (2010)

    CAS  Article  Google Scholar 

  12. Blenkiron, C. et al. MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype. Genome Biol. 8, R214 (2007)

    Article  Google Scholar 

  13. Luqmani, Y. A., Al Azmi, A., Al Bader, M., Abraham, G. & El Zawahri, M. Modification of gene expression induced by siRNA targeting of estrogen receptor α in MCF7 human breast cancer cells. Int. J. Oncol. 34, 231–242 (2009)

    CAS  Google Scholar 

  14. Seitz, H. et al. A large imprinted microRNA gene cluster at the mouse Dlk1-Gtl2 domain. Genome Res. 14, 1741–1748 (2004)

    CAS  Article  Google Scholar 

  15. Krol, J., Loedige, I. & Filipowicz, W. The widespread regulation of microRNA biogenesis, function and decay. Nature Rev. Genet. 11, 597–610 (2010)

    CAS  Article  Google Scholar 

  16. Bezman, N. A., Chakraborty, T., Bender, T. & Lanier, L. L. miR-150 regulates the development of NK and iNKT cells. J. Exp. Med. 208, 2717–2731 (2011)

    CAS  Article  Google Scholar 

  17. Faraoni, I., Antonetti, F. R., Cardone, J. & Bonmassar, E. miR-155 gene: a typical multifunctional microRNA. Biochim. Biophys. Acta 1792, 497–505 (2009)

    CAS  Article  Google Scholar 

  18. Xu, W. D., Lu, M. M., Pan, H. F. & Ye, D. Q. Association of microRNA-146a with Autoimmune Diseases. Inflammation 35, 1525–1529 (2012)

    CAS  Article  Google Scholar 

  19. Andreopoulos, B. & Anastassiou, D. Integrated analysis reveals hsa-miR-142 as a representative of a lymphocyte-specific gene expression and methylation signature. Cancer Inform. 11, 61–75 (2012)

    CAS  Article  Google Scholar 

  20. Teschendorff, A. E., Miremadi, A., Pinder, S. E., Ellis, I. O. & Caldas, C. An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer. Genome Biol. 8, R157 (2007)

    Article  Google Scholar 

  21. Peng, X. et al. Identification of miRs-143 and -145 that is associated with bone metastasis of prostate cancer and involved in the regulation of EMT. PLoS ONE 6, e20341 (2011)

    CAS  ADS  Article  Google Scholar 

  22. Li, B. et al. Down-regulation of miR-214 contributes to intrahepatic cholangiocarcinoma metastasis by targeting Twist. FEBS J. 279, 2393–2398 (2012)

    CAS  Article  Google Scholar 

  23. Git, A. et al. PMC42, a breast progenitor cancer cell line, has normal-like mRNA and microRNA transcriptomes. Breast Cancer Res. 10, R54 (2008)

    Article  Google Scholar 

  24. Guo, H., Hu, X., Ge, S., Qian, G. & Zhang, J. Regulation of RAP1B by miR-139 suppresses human colorectal carcinoma cell proliferation. Int. J. Biochem. Cell Biol. 44, 1465–1472 (2012)

    CAS  Article  Google Scholar 

  25. Castellano, L. et al. The estrogen receptor-α-induced microRNA signature regulates itself and its transcriptional response. Proc. Natl Acad. Sci. USA 106, 15732–15737 (2009)

    CAS  ADS  Article  Google Scholar 

  26. Boquest, A. C. et al. Isolation and transcription profiling of purified uncultured human stromal stem cells: alteration of gene expression after in vitro cell culture. Mol. Biol. Cell 16, 1131–1141 (2005)

    CAS  Article  Google Scholar 

  27. Scheel, C. et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 145, 926–940 (2011)

    CAS  Article  Google Scholar 

  28. Schmidt, W. M., Spiel, A. O., Jilma, B., Wolzt, M. & Muller, M. In vivo profile of the human leukocyte microRNA response to endotoxemia. Biochem. Biophys. Res. Commun. 380, 437–441 (2009)

    CAS  Article  Google Scholar 

  29. Bair, E. & Tibshirani, R. Semi-supervised methods to predict patient survival from gene expression data. PLoS Biol. 2, e108 (2004)

    Article  Google Scholar 

  30. Fabbri, M. et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc. Natl Acad. Sci. USA 109, E2110–E2116 (2012)

    CAS  Article  Google Scholar 

Download references


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 in sample management; S. Fulmer-Smentek and T. Hill for help with 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 are very grateful to the patients who donated tissue and associated pseudo-anonymized clinical data.

Author information

Authors and Affiliations



H.D. and A.Git led the analysis and drafted the manuscript with C.Caldas; A.Git, S.G., S.A. and C.Caldas designed and coordinated the study; A.Git carried out all microarray and quantitative reverse transcriptase PCR laboratory work. Sequencing data were provided by Y.Z., M.H., J.A., E.A.M. and S.A. and analysed by M.S.-D., who also analysed external epigenetic data; S.G. designed custom microarray probes and contributed to array pre-processing. C.Curtis and A.S. processed external CNA data. S.-F.C., E.P., A.Green, I.E., G.T., S.A. and C.Caldas coordinated collection and processing of clinical material and associated clinical and histopathological information. S.A. and C.Caldas are joint senior authors and project co-leaders.

Corresponding authors

Correspondence to Anna Git, Sam Aparicio or Carlos Caldas.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Methods, Supplementary Appendix containing R source code for the modulatory effect of miRNAs, Supplementary References and Supplementary Figures 1-8. (PDF 8229 kb)

Supplementary Data

This file contains Supplementary Tables 1-9. Supplementary Table 1 contains detailed clinical and histopathological information for the 1,302 tumors; Supplementary Table 2 shows annotation, potential cross-hybridization and distribution of 853 detectable miRNAs; Supplementary Table 3 shows miRNAs regulated by CNAs across the entire cohort or in ER+/ER- sub-cohorts; Supplementary Table 4 contains a list of minimal common regions of CNAs (across the entire cohort or in ER+/ER- sub-cohorts) which contain miRNAs and mRNAs; Supplementary Table 4 contains a list of minimal common regions of CNAs (across the entire cohort or in ER+/ER- sub-cohorts) which contain only miRNAs; Supplementary Table 5 shows intensity and correlation of detectable sibling miRNAs; Supplementary Table 6 contains a list of differentially expressed miRNAs between ER+ and ER- sub-cohorts or between Pam50 subtypes; Supplementary Table 7 shows calculated pairwise generalized additive model values for variable mRNAs and miRNAs; Supplementary Table 8 contains a list of significantly enriched Gene Ontology Biological Process terms in mRNAs clustered by miRNA-mRNA GAM values and Supplementary Table 9 contains a summary of ER and Her2 statuses of the breast cancer cell lines used in this study. (ZIP 3021 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Dvinge, H., Git, A., Gräf, S. et al. The shaping and functional consequences of the microRNA landscape in breast cancer. Nature 497, 378–382 (2013).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer