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.
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Gene Expression Omnibus
The miR-335 microarray data is deposited at GEO under accession number GSE9586.
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.
This file contains Supplementary Figures 1-15 with Legends.
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.