Skip to main content

Thank you for visiting nature.com. 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.

Endogenous human microRNAs that suppress breast cancer metastasis

Nature volume 451, pages 147–152 (2008)Cite this article

Abstract

A search for general regulators of cancer metastasis has yielded a set of microRNAs for which expression is specifically lost as human breast cancer cells develop metastatic potential. Here we show that restoring the expression of these microRNAs in malignant cells suppresses lung and bone metastasis by human cancer cells in vivo. Of these microRNAs, miR-126 restoration reduces overall tumour growth and proliferation, whereas miR-335 inhibits metastatic cell invasion. miR-335 regulates a set of genes whose collective expression in a large cohort of human tumours is associated with risk of distal metastasis. miR-335 suppresses metastasis and migration through targeting of the progenitor cell transcription factor SOX4 and extracellular matrix component tenascin C. Expression of miR-126 and miR-335 is lost in the majority of primary breast tumours from patients who relapse, and the loss of expression of either microRNA is associated with poor distal metastasis-free survival. miR-335 and miR-126 are thus identified as metastasis suppressor microRNAs 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

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Systematic identification of miRNAs that suppress lung and bone metastasis in multiple human breast cancer cell derivatives.
Figure 2: miR-126 suppresses overall tumour growth and proliferation whereas miR-335 and miR-206 regulate migration and morphology.
Figure 3: Clinical association of miR-335 and miR-126 with metastasis-free survival.
Figure 4: A miR-335-regulated gene set includes SOX4 as a miR-335 direct target.
Figure 5: miR-335 regulates metastasis and invasion through suppression of SOX4 and TNC.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

The miR-335 microarray data is deposited at GEO under accession number GSE9586.

References

  1. Fidler, I. J. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nature Rev. Cancer 3, 453–458 (2003)

    Article  ADS  CAS  Google Scholar 

  2. Weigelt, B., Peterse, J. L. & van‘t Veer, L. J. Breast cancer metastasis: markers and models. Nature Rev. Cancer 5, 591–602 (2005)

    Article  CAS  Google Scholar 

  3. Gupta, G. P. & Massague, J. Cancer metastasis: building a framework. Cell 127, 679–695 (2006)

    Article  CAS  Google Scholar 

  4. Nevins, J. R. & Potti, A. Mining gene expression profiles: expression signatures as cancer phenotypes. Nature Rev. Genet. 8, 601–609 (2007)

    Article  CAS  Google Scholar 

  5. Nguyen, D. X. & Massague, J. Genetic determinants of cancer metastasis. Nature Rev. Genet. 8, 341–352 (2007)

    Article  CAS  Google Scholar 

  6. Gupta, G. P. et al. Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446, 765–770 (2007)

    Article  ADS  CAS  Google Scholar 

  7. Seligson, D. B. et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435, 1262–1266 (2005)

    Article  ADS  CAS  Google Scholar 

  8. Lim, L. P. et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433, 769–773 (2005)

    Article  ADS  CAS  Google Scholar 

  9. Chan, C. S., Elemento, O. & Tavazoie, S. Revealing posttranscriptional regulatory elements through network-level conservation. PLoS Comput. Biol. 1, e69 (2005)

    Article  ADS  Google Scholar 

  10. Voorhoeve, P. M. et al. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell 124, 1169–1181 (2006)

    Article  CAS  Google Scholar 

  11. Kumar, M. S., Lu, J., Mercer, K. L., Golub, T. R. & Jacks, T. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nature Genet. 39, 673–677 (2007)

    Article  CAS  Google Scholar 

  12. Ma, L., Teruya-Feldstein, J. & Weinberg, R. A. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449, 682–688 (2007)

    Article  ADS  CAS  Google Scholar 

  13. Lu, J. et al. MicroRNA expression profiles classify human cancers. Nature 435, 834–838 (2005)

    Article  ADS  CAS  Google Scholar 

  14. Calin, G. A. et al. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc. Natl Acad. Sci. USA 101, 11755–11760 (2004)

    Article  ADS  CAS  Google Scholar 

  15. Chen, C. Z., Li, L., Lodish, H. F. & Bartel, D. P. MicroRNAs modulate hematopoietic lineage differentiation. Science 303, 83–86 (2004)

    Article  ADS  CAS  Google Scholar 

  16. Meister, G., Landthaler, M., Dorsett, Y. & Tuschl, T. Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing. RNA 10, 544–550 (2004)

    Article  CAS  Google Scholar 

  17. Kang, Y. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537–549 (2003)

    Article  CAS  Google Scholar 

  18. Minn, A. J. et al. Genes that mediate breast cancer metastasis to lung. Nature 436, 518–524 (2005)

    Article  ADS  CAS  Google Scholar 

  19. Egeblad, M. et al. Type I collagen is a genetic modifier of matrix metalloproteinase 2 in murine skeletal development. Dev. Dyn. 236, 1683–1693 (2007)

    Article  CAS  Google Scholar 

  20. Varadi, A., Tsuboi, T. & Rutter, G. A. Myosin Va transports dense core secretory vesicles in pancreatic MIN6 beta-cells. Mol. Biol. Cell 16, 2670–2680 (2005)

    Article  CAS  Google Scholar 

  21. Graham, D. K. et al. Cloning and developmental expression analysis of the murine c-mer tyrosine kinase. Oncogene 10, 2349–2359 (1995)

    CAS  PubMed  Google Scholar 

  22. Lyu, M. S., Park, D. J., Rhee, S. G. & Kozak, C. A. Genetic mapping of the human and mouse phospholipase C genes. Mamm. Genome 7, 501–504 (1996)

    Article  CAS  Google Scholar 

  23. Ilunga, K. et al. Co-stimulation of human breast cancer cells with transforming growth factor-β and tenascin-C enhances matrix metalloproteinase-9 expression and cancer cell invasion. Int. J. Exp. Pathol. 85, 373–379 (2004)

    Article  CAS  Google Scholar 

  24. van de Wetering, M., Oosterwegel, M., van Norren, K. & Clevers, H. Sox-4, an Sry-like HMG box protein, is a transcriptional activator in lymphocytes. EMBO J. 12, 3847–3854 (1993)

    Article  CAS  Google Scholar 

  25. Hoser, M. et al. Prolonged glial expression of Sox4 in the CNS leads to architectural cerebellar defects and ataxia. J. Neurosci. 27, 5495–5505 (2007)

    Article  CAS  Google Scholar 

  26. Orend, G. & Chiquet-Ehrismann, R. Tenascin-C induced signaling in cancer. Cancer Lett. 244, 143–163 (2006)

    Article  CAS  Google Scholar 

  27. Wang, Y. et al. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365, 671–679 (2005)

    Article  CAS  Google Scholar 

  28. Schilham, M. W., Moerer, P., Cumano, A. & Clevers, H. C. Sox-4 facilitates thymocyte differentiation. Eur. J. Immunol. 27, 1292–1295 (1997)

    Article  CAS  Google Scholar 

  29. Steeg, P. S. Metastasis suppressors alter the signal transduction of cancer cells. Nature Rev. Cancer 3, 55–63 (2003)

    Article  CAS  Google Scholar 

  30. Minn, A. J. et al. Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J. Clin. Invest. 115, 44–55 (2005)

    Article  CAS  Google Scholar 

  31. Gomis, R. R., Alarcon, C., Nadal, C., Van Poznak, C. & Massague, J. C/EBPβ at the core of the TGFβ cytostatic response and its evasion in metastatic breast cancer cells. Cancer Cell 10, 203–214 (2006)

    Article  CAS  Google Scholar 

  32. Chen, C. et al. Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res. 33, e179 (2005)

    Article  Google Scholar 

  33. He, L. et al. A microRNA component of the p53 tumour suppressor network. Nature 447, 1130–1134 (2007)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Tavazoie, M. Tavazoie, D. Nguyen, S. Kurdistani and X. Zhang for discussions and technical suggestions. We are grateful to R. Agami, C. Le Sage and R. Nagel for providing the miR-Vec constructs. We thank J. Baez, E. Montalvo, E. Suh, Z. Lazar, Y. Romin, A. Barlas, K. Manova-Todorova and members of the Molecular Cytology Core Facility. We thank X. Zhou of LC Sciences for miRNA profiling services as well as the MSKCC core facility for transcriptional profiling. J.M. was funded by a National Institutes of Health grant, and by grants of the Hearst Foundation and the Kleberg Foundation. S.F.T. is supported by the Olson Foundation grant and a Clinical Scholars Award. J.M. is an Investigator of the Howard Hughes Medical Institute.

Author Contributions S.F.T. and J.M. designed experiments. J.M. supervised research. S.F.T. and J.M. wrote the manuscript. S.F.T. performed experiments. C.A. helped with UTR cloning and reporter experiments and performed confocal microscopy. T.O. helped with TNC experiments. D.P. assisted with mammary fat pad experiments and lung extractions. Q.W. assisted with intracardiac injections. P.D.B. generated and validated TNC shRNA. W.L.G. obtained, classified and processed breast tumour samples. All authors discussed the results and commented on the manuscript.

Author information

Authors and Affiliations

  1. Cancer Biology and Genetics Program,,

    Sohail F. Tavazoie, Claudio Alarcón, Thordur Oskarsson, David Padua, Qiongqing Wang, Paula D. Bos & Joan Massagué

  2. Department of Medicine,,

    Sohail F. Tavazoie

  3. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA,

    William L. Gerald

Authors
  1. Sohail F. Tavazoie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claudio Alarcón
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thordur Oskarsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Padua
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qiongqing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paula D. Bos
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. William L. Gerald
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Joan Massagué
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joan Massagué.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-15 with Legends. (PDF 13435 kb)

Supplementary Tables

This file contains Supplementary Table 1 which contains staging and histological features of primary breast tumours whose miRNA expression were analyzed and Supplementary Table 2 which contains the names and probe ID’s of genes upregulated in both lung and bone metastatic cells. (PDF 53 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Tavazoie, S., Alarcón, C., Oskarsson, T. et al. Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451, 147–152 (2008). https://doi.org/10.1038/nature06487

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06487

This article is cited by

Comments

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.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing