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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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.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
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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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