title: Local microRNA delivery targets Palladin and prevents metastatic breast cancer.
abstract: Metastasis is the primary cause for mortality in breast cancer. MicroRNAs, gene expression master regulators, constitute an attractive candidate to control metastasis. Here we show that breast cancer metastasis can be prevented by miR-96 or miR-182 treatment, and decipher the mechanism of action. We found that miR-96/miR-182 downregulate Palladin protein levels, thereby reducing breast cancer cell migration and invasion. A common SNP, rs1071738, at the miR-96/miR-182-binding site within the Palladin 3'-UTR abolishes miRNA:mRNA binding, thus diminishing Palladin regulation by these miRNAs. Regulation is successfully restored by applying complimentary miRNAs. A hydrogel-embedded, gold-nanoparticle-based delivery vehicle provides efficient local, selective, and sustained release of miR-96/miR-182, markedly suppressing metastasis in a breast cancer mouse model. Combined delivery of the miRNAs with a chemotherapy drug, cisplatin, enables significant primary tumour shrinkage and metastasis prevention. Our data corroborate the role of miRNAs in metastasis, and suggest miR-96/miR-182 delivery as a potential anti-metastatic drug.
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.
authors.forename: Avital
authors.initials: A
authors.lastname: Gilam
authors.affiliation: Massachusetts Institute of Technology, Institute for Medical Engineering and Science, Cambridge, Massachusetts 02139, USA.|School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, UK.
authors.forename: João
authors.initials: J
authors.lastname: Conde
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.
authors.forename: Daphna
authors.initials: D
authors.lastname: Weissglas-Volkov
authors.affiliation: Massachusetts Institute of Technology, Institute for Medical Engineering and Science, Cambridge, Massachusetts 02139, USA.
authors.forename: Nuria
authors.initials: N
authors.lastname: Oliva
authors.affiliation: The Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center Tel-Hashomer, 52621 Ramat Gan, Israel.
authors.forename: Eitan
authors.initials: E
authors.lastname: Friedman
authors.affiliation: Massachusetts Institute of Technology, Institute for Medical Engineering and Science, Cambridge, Massachusetts 02139, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Department of Medicine, Biomedical Engineering Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Artzi
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.
authors.forename: Noam
authors.initials: N
authors.lastname: Shomron
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000378:metabolism / Q000627:therapeutic use*; D009362:Neoplasm Metastasis; D010750:Phosphoproteins / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D023041:Xenograft Model Antitumor Assays
chemical_list: D003598:Cytoskeletal Proteins; C541492:MIRN96 microRNA, human; D035683:MicroRNAs; C540524:Mirn182 microRNA, mouse; C412722:PALLD protein, human; D010750:Phosphoproteins