Activation of miR-31 function in already-established metastases elicits metastatic regression
- Scott Valastyan1,2,
- Amelia Chang1,2,
- Nathan Benaich1,
- Ferenc Reinhardt1 and
- Robert A. Weinberg1,2,3,4
- 1Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA;
- 2Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 3Massachusetts Institute of Technology Ludwig Center for Molecular Oncology, Cambridge, Massachusetts 02139, USA
Abstract
Distant metastases, rather than the primary tumors from which these lesions arise, are responsible for >90% of carcinoma-associated mortality. Many patients already harbor disseminated tumor cells in their bloodstream, bone marrow, and distant organs when they initially present with cancer. Hence, truly effective anti-metastatic therapeutics must impair the proliferation and survival of already-established metastases. Here, we assess the therapeutic potential of acutely expressing the microRNA miR-31 in already-formed breast cancer metastases. Activation of miR-31 in established metastases elicits metastatic regression and prolongs survival. Remarkably, even brief induction of miR-31 in macroscopic pulmonary metastases diminishes metastatic burden. In contrast, acute miR-31 expression fails to affect primary mammary tumor growth. miR-31 triggers metastatic regression in the lungs by eliciting cell cycle arrest and apoptosis; these responses occur specifically in metastases and can be explained by miR-31-mediated suppression of integrin-α5, radixin, and RhoA. Indeed, concomitant re-expression of these three proteins renders already-seeded pulmonary metastases refractory to miR-31-conferred regression. Upon miR-31 activation, Akt-dependent signaling is attenuated and the proapoptotic molecule Bim is induced; these effects occur in a metastasis-specific manner in pulmonary lesions and are abrogated by concurrent re-expression of integrin-α5, radixin, and RhoA. Collectively, these findings raise the possibility that intervention strategies centered on restoring miR-31 function may prove clinically useful for combating metastatic disease.
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Footnotes
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↵4 Corresponding author.
E-MAIL weinberg{at}wi.mit.edu; FAX (617) 258-5213.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.2004211.
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Supplemental material is available for this article.
- Received October 18, 2010.
- Accepted January 31, 2011.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press