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Tumour invasion and metastasis initiated by microRNA-10b in breast cancer

Nature volume 449, pages 682–688 (2007)Cite this article

An Erratum to this article was published on 11 September 2008

Abstract

MicroRNAs have been implicated in regulating diverse cellular pathways. Although there is emerging evidence that some microRNAs can function as oncogenes or tumour suppressors, the role of microRNAs in mediating cancer metastasis remains unexplored. Here we show, using a combination of mouse and human cells, that microRNA-10b (miR-10b) is highly expressed in metastatic breast cancer cells and positively regulates cell migration and invasion. Overexpression of miR-10b in otherwise non-metastatic breast tumours initiates robust invasion and metastasis. Expression of miR-10b is induced by the transcription factor Twist, which binds directly to the putative promoter of mir-10b (MIRN10B). The miR-10b induced by Twist proceeds to inhibit translation of the messenger RNA encoding homeobox D10, resulting in increased expression of a well-characterized pro-metastatic gene, RHOC. Significantly, the level of miR-10b expression in primary breast carcinomas correlates with clinical progression. These findings suggest the workings of an undescribed regulatory pathway, in which a pleiotropic transcription factor induces expression of a specific microRNA, which suppresses its direct target and in turn activates another pro-metastatic gene, leading to tumour cell invasion and metastasis.

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Figure 1: miR-10b is highly expressed in metastatic breast cancer cells and positively regulates cell migration and invasion.
Figure 2: miR-10b induces tumour invasion.
Figure 3: miR-10b induces distant metastasis.
Figure 4: miR-10b is regulated by Twist.
Figure 5: miR-10b suppresses HOXD10, leading to induction of RHOC.
Figure 6: miR-10b expression level is associated with the metastasis outcome in breast cancer patients.

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References

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

    CAS  Google Scholar 

  2. Batlle, E. et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nature Cell Biol. 2, 84–89 (2000)

    CAS  Google Scholar 

  3. Cano, A. et al. The transcription factor snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression. Nature Cell Biol. 2, 76–83 (2000)

    CAS  Google Scholar 

  4. Comijn, J. et al. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol. Cell 7, 1267–1278 (2001)

    CAS  Google Scholar 

  5. Bolos, V. et al. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J. Cell Sci. 116, 499–511 (2003)

    CAS  Google Scholar 

  6. Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004)

    CAS  Google Scholar 

  7. Hartwell, K. A. et al. The Spemann organizer gene, Goosecoid, promotes tumor metastasis. Proc. Natl Acad. Sci. USA 103, 18969–18974 (2006)

    CAS  Google Scholar 

  8. Mani, S. A. et al. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc. Natl Acad. Sci. USA 104, 10069–10074 (2007)

    CAS  Google Scholar 

  9. Calin, G. A. & Croce, C. M. MicroRNA signatures in human cancers. Nature Rev. Cancer 6, 857–866 (2006)

    CAS  Google Scholar 

  10. Esquela-Kerscher, A. & Slack, F. J. Oncomirs — microRNAs with a role in cancer. Nature Rev. Cancer 6, 259–269 (2006)

    CAS  Google Scholar 

  11. Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004)

    CAS  Google Scholar 

  12. Brennecke, J., Hipfner, D. R., Stark, A., Russell, R. B. & Cohen, S. M. bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila . Cell 113, 25–36 (2003)

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  14. Poy, M. N. et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432, 226–230 (2004)

    CAS  Google Scholar 

  15. Yi, R. et al. Morphogenesis in skin is governed by discrete sets of differentially expressed microRNAs. Nature Genet. 38, 356–362 (2006)

    CAS  Google Scholar 

  16. Schratt, G. M. et al. A brain-specific microRNA regulates dendritic spine development. Nature 439, 283–289 (2006)

    CAS  Google Scholar 

  17. Calin, G. A. et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc. Natl Acad. Sci. USA 101, 2999–3004 (2004)

    CAS  Google Scholar 

  18. He, L. et al. A microRNA polycistron as a potential human oncogene. Nature 435, 828–833 (2005)

    CAS  Google Scholar 

  19. Johnson, S. M. et al. RAS is regulated by the let-7 microRNA family. Cell 120, 635–647 (2005)

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  21. Roldo, C. et al. MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. J. Clin. Oncol. 24, 4677–4684 (2006)

    CAS  Google Scholar 

  22. Iorio, M. V. et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 65, 7065–7070 (2005)

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  24. Cheng, A. M., Byrom, M. W., Shelton, J. & Ford, L. P. Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res. 33, 1290–1297 (2005)

    CAS  Google Scholar 

  25. Elenbaas, B. et al. Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. Genes Dev. 15, 50–65 (2001)

    CAS  Google Scholar 

  26. Ethier, S. P., Mahacek, M. L., Gullick, W. J., Frank, T. S. & Weber, B. L. Differential isolation of normal luminal mammary epithelial cells and breast cancer cells from primary and metastatic sites using selective media. Cancer Res. 53, 627–635 (1993)

    CAS  Google Scholar 

  27. Kuperwasser, C. et al. A mouse model of human breast cancer metastasis to human bone. Cancer Res. 65, 6130–6138 (2005)

    CAS  Google Scholar 

  28. Thiery, J. P. Epithelial–mesenchymal transitions in tumour progression. Nature Rev. Cancer 2, 442–454 (2002)

    CAS  Google Scholar 

  29. Cripps, R. M. et al. The myogenic regulatory gene Mef2 is a direct target for transcriptional activation by Twist during Drosophila myogenesis. Genes Dev. 12, 422–434 (1998)

    CAS  Google Scholar 

  30. Cheng, G. Z. et al. Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cancer Res. 67, 1979–1987 (2007)

    CAS  Google Scholar 

  31. Zhou, X., Ruan, J., Wang, G. & Zhang, W. Characterization and identification of microRNA core promoters in four model species. PLoS Comput. Biol. 3, e37 (2007)

    Google Scholar 

  32. Lewis, B. P., Shih, I. H., Jones-Rhoades, M. W., Bartel, D. P. & Burge, C. B. Prediction of mammalian microRNA targets. Cell 115, 787–798 (2003)

    CAS  Google Scholar 

  33. Krek, A. et al. Combinatorial microRNA target predictions. Nature Genet. 37, 495–500 (2005)

    CAS  Google Scholar 

  34. Makiyama, K. et al. Aberrant expression of HOX genes in human invasive breast carcinoma. Oncol. Rep. 13, 673–679 (2005)

    CAS  Google Scholar 

  35. Carrio, M., Arderiu, G., Myers, C. & Boudreau, N. J. Homeobox D10 induces phenotypic reversion of breast tumor cells in a three-dimensional culture model. Cancer Res. 65, 7177–7185 (2005)

    CAS  Google Scholar 

  36. Myers, C., Charboneau, A., Cheung, I., Hanks, D. & Boudreau, N. Sustained expression of homeobox D10 inhibits angiogenesis. Am. J. Pathol. 161, 2099–2109 (2002)

    CAS  Google Scholar 

  37. Clark, E. A., Golub, T. R., Lander, E. S. & Hynes, R. O. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406, 532–535 (2000)

    CAS  Google Scholar 

  38. Hakem, A. et al. RhoC is dispensable for embryogenesis and tumor initiation but essential for metastasis. Genes Dev. 19, 1974–1979 (2005)

    CAS  Google Scholar 

  39. Kleer, C. G. et al. RhoC GTPase expression as a potential marker of lymph node metastasis in squamous cell carcinomas of the head and neck. Clin. Cancer Res. 12, 4485–4490 (2006)

    CAS  Google Scholar 

  40. Kondo, T. et al. Expression of RhoC is associated with metastasis of gastric carcinomas. Pathobiology 71, 19–25 (2004)

    Google Scholar 

  41. Wang, W. et al. Overexpression of the RhoC gene correlates with invasion and metastasis of hepatocellular carcinoma Chinese J. Oncol . (Zhonghua Zhong Liu Za Zhi.) 26, 279–282 (2004)

  42. Reichmann, E. et al. Activation of an inducible c-FosER fusion protein causes loss of epithelial polarity and triggers epithelial–fibroblastoid cell conversion. Cell 71, 1103–1116 (1992)

    CAS  Google Scholar 

  43. Enright, A. J. et al. MicroRNA targets in Drosophila . Genome Biol. 5, R1 (2003)

    Google Scholar 

  44. Yekta, S., Shih, I. H. & Bartel, D. P. MicroRNA-directed cleavage of HOXB8 mRNA. Science 304, 594–596 (2004)

    CAS  Google Scholar 

  45. Ronshaugen, M., Biemar, F., Piel, J., Levine, M. & Lai, E. C. The Drosophila microRNA iab-4 causes a dominant homeotic transformation of halteres to wings. Genes Dev. 19, 2947–2952 (2005)

    CAS  Google Scholar 

  46. Garzon, R. et al. MicroRNA fingerprints during human megakaryocytopoiesis. Proc. Natl Acad. Sci. USA 103, 5078–5083 (2006)

    CAS  Google Scholar 

  47. Zhang, X. et al. Human growth hormone-regulated HOXA1 is a human mammary epithelial oncogene. J. Biol. Chem. 278, 7580–7590 (2003)

    CAS  Google Scholar 

  48. Stewart, S. A. et al. Lentivirus-delivered stable gene silencing by RNAi in primary cells. RNA 9, 493–501 (2003)

    CAS  Google Scholar 

Download references

Acknowledgements

We thank D. Bartel, H. Lodish, P. Rao, B. Zhou, S. Mani, J. Yang, S. Ethier, C. Largman and L.-H. Wang for reagents and advice; F. Reinhardt for assistance with animal experiments; the Histology Core Laboratory at MIT and MSKCC for assistance with sectioning and immunohistochemistry; C. Mayr, C. Scheel, S. McAllister, I. Ben-Porath, Y. Sun and Y. Luo for critical reading of the manuscript; and members of the Weinberg Laboratory for useful discussions. L.M. is a Susan G. Komen Fellow of the Life Sciences Research Foundation. J.T.-F. is supported by the MSKCC Cancer Core Grant. R.A.W. is an American Cancer Society Research Professor and a Daniel K. Ludwig Cancer Research Professor. This research is supported by an NIH grant (R.A.W.) and the Ludwig Center for Molecular Oncology at MIT.

Author Contributions L.M. conceived the project. R.A.W. supervised research. L.M. designed and performed experiments. L.M. and J.T.-F. collected and analysed data. All authors contributed to the preparation of the manuscript.

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  1. Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA,

    Li Ma & Robert A. Weinberg

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

    Julie Teruya-Feldstein

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  1. Li Ma
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Correspondence to Robert A. Weinberg.

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Ma, L., Teruya-Feldstein, J. & Weinberg, R. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449, 682–688 (2007). https://doi.org/10.1038/nature06174

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