Article | Published:

Endogenous human microRNAs that suppress breast cancer metastasis

Nature volume 451, pages 147152 (10 January 2008) | Download Citation


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


Primary accessions

Gene Expression Omnibus

Data deposits

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


  1. 1.

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

  2. 2.

    , & Breast cancer metastasis: markers and models. Nature Rev. Cancer 5, 591–602 (2005)

  3. 3.

    & Cancer metastasis: building a framework. Cell 127, 679–695 (2006)

  4. 4.

    & Mining gene expression profiles: expression signatures as cancer phenotypes. Nature Rev. Genet. 8, 601–609 (2007)

  5. 5.

    & Genetic determinants of cancer metastasis. Nature Rev. Genet. 8, 341–352 (2007)

  6. 6.

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

  7. 7.

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

  8. 8.

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

  9. 9.

    , & Revealing posttranscriptional regulatory elements through network-level conservation. PLoS Comput. Biol. 1, e69 (2005)

  10. 10.

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

  11. 11.

    , , , & Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nature Genet. 39, 673–677 (2007)

  12. 12.

    , & Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449, 682–688 (2007)

  13. 13.

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

  14. 14.

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

  15. 15.

    , , & MicroRNAs modulate hematopoietic lineage differentiation. Science 303, 83–86 (2004)

  16. 16.

    , , & Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing. RNA 10, 544–550 (2004)

  17. 17.

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

  18. 18.

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

  19. 19.

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

  20. 20.

    , & Myosin Va transports dense core secretory vesicles in pancreatic MIN6 beta-cells. Mol. Biol. Cell 16, 2670–2680 (2005)

  21. 21.

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

  22. 22.

    , , & Genetic mapping of the human and mouse phospholipase C genes. Mamm. Genome 7, 501–504 (1996)

  23. 23.

    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)

  24. 24.

    , , & Sox-4, an Sry-like HMG box protein, is a transcriptional activator in lymphocytes. EMBO J. 12, 3847–3854 (1993)

  25. 25.

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

  26. 26.

    & Tenascin-C induced signaling in cancer. Cancer Lett. 244, 143–163 (2006)

  27. 27.

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

  28. 28.

    , , & Sox-4 facilitates thymocyte differentiation. Eur. J. Immunol. 27, 1292–1295 (1997)

  29. 29.

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

  30. 30.

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

  31. 31.

    , , , & C/EBPβ at the core of the TGFβ cytostatic response and its evasion in metastatic breast cancer cells. Cancer Cell 10, 203–214 (2006)

  32. 32.

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

  33. 33.

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

Download references


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


  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


  1. Search for Sohail F. Tavazoie in:

  2. Search for Claudio Alarcón in:

  3. Search for Thordur Oskarsson in:

  4. Search for David Padua in:

  5. Search for Qiongqing Wang in:

  6. Search for Paula D. Bos in:

  7. Search for William L. Gerald in:

  8. Search for Joan Massagué in:

Corresponding author

Correspondence to Joan Massagué.

Supplementary information

PDF files

  1. 1.

    Supplementary Figures

    This file contains Supplementary Figures 1-15 with Legends.

  2. 2.

    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.

About this article

Publication history





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.