A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis.
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.
Valastyan
Scott
S
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Reinhardt
Ferenc
F
Benaich
Nathan
N
Calogrias
Diana
D
Szász
Attila M
AM
Wang
Zhigang C
ZC
Brock
Jane E
JE
Richardson
Andrea L
AL
Weinberg
Robert A
RA
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
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