title: A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis.
abstract: MicroRNAs are well suited to regulate tumor metastasis because of their capacity to coordinately repress numerous target genes, thereby potentially enabling their intervention at multiple steps of the invasion-metastasis cascade. We identify a microRNA exemplifying these attributes, miR-31, whose expression correlates inversely with metastasis in human breast cancer patients. Overexpression of miR-31 in otherwise-aggressive breast tumor cells suppresses metastasis. We deploy a stable microRNA sponge strategy to inhibit miR-31 in vivo; this allows otherwise-nonaggressive breast cancer cells to metastasize. These phenotypes do not involve confounding influences on primary tumor development and are specifically attributable to miR-31-mediated inhibition of several steps of metastasis, including local invasion, extravasation or initial survival at a distant site, and metastatic colonization. Such pleiotropy is achieved via coordinate repression of a cohort of metastasis-promoting genes, including RhoA. Indeed, RhoA re-expression partially reverses miR-31-imposed metastasis suppression. These findings indicate that miR-31 uses multiple mechanisms to oppose metastasis.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Valastyan
authors.forename: Ferenc
authors.initials: F
authors.lastname: Reinhardt
authors.forename: Nathan
authors.initials: N
authors.lastname: Benaich
authors.forename: Diana
authors.initials: D
authors.lastname: Calogrias
authors.forename: Attila M
authors.initials: AM
authors.lastname: Szász
authors.forename: Zhigang C
authors.initials: ZC
authors.lastname: Wang
authors.forename: Jane E
authors.initials: JE
authors.lastname: Brock
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.forename: Robert A
authors.initials: RA
authors.lastname: Weinberg
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000235:genetics; D051157:Frizzled Receptors / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039482:Integrin alpha5 / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D035683:MicroRNAs / Q000378:metabolism*; D009362:Neoplasm Metastasis; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D020742:rhoA GTP-Binding Protein / Q000235:genetics
chemical_list: D003598:Cytoskeletal Proteins; C105574:FZD3 protein, human; D051157:Frizzled Receptors; D039482:Integrin alpha5; C534612:MIRN31 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C539917:Mirn31 microRNA, mouse; D043562:Receptors, G-Protein-Coupled; C071776:radixin; D020742:rhoA GTP-Binding Protein