title: Activation of miR-31 function in already-established metastases elicits metastatic regression.
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.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Valastyan
authors.forename: Amelia
authors.initials: A
authors.lastname: Chang
authors.forename: Nathan
authors.initials: N
authors.lastname: Benaich
authors.forename: Ferenc
authors.initials: F
authors.lastname: Reinhardt
authors.forename: Robert A
authors.initials: RA
authors.lastname: Weinberg
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001943:Breast Neoplasms / Q000503:physiopathology*; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000503:physiopathology* / Q000628:therapy; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D003598:Cytoskeletal Proteins; C534612:MIRN31 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; C071776:radixin; D051057:Proto-Oncogene Proteins c-akt; D020742:rhoA GTP-Binding Protein