title: Antagonizing miR-218-5p attenuates Wnt signaling and reduces metastatic bone disease of triple negative breast cancer cells.
abstract: Wnt signaling is implicated in bone formation and activated in breast cancer cells promoting primary and metastatic tumor growth. A compelling question is whether osteogenic miRNAs that increase Wnt activity for bone formation are aberrantly expressed in breast tumor cells to support metastatic bone disease. Here we report that miR-218-5p is highly expressed in bone metastases from breast cancer patients, but is not detected in normal mammary epithelial cells. Furthermore, inhibition of miR-218-5p impaired the growth of bone metastatic MDA-MB-231 cells in the bone microenvironment in vivo. These findings indicate a positive role for miR-218-5p in bone metastasis. Bioinformatic and biochemical analyses revealed a positive correlation between aberrant miR-218-5p expression and activation of Wnt signaling in breast cancer cells. Mechanistically, miR-218-5p targets the Wnt inhibitors Sclerostin (SOST) and sFRP-2, which highly enhances Wnt signaling. In contrast, delivery of antimiR-218-5p decreased Wnt activity and the expression of metastasis-related genes, including bone sialoprotein (BSP/IBSP), osteopontin (OPN/SPP1) and CXCR-4, implicating a Wnt/miR-218-5p regulatory network in bone metastatic breast cancer. Furthermore, miR-218-5p also mediates the Wnt-dependent up-regulation of PTHrP, a key cytokine promoting cancer-induced osteolysis. Antagonizing miR-218-5p reduced the expression of PTHrP and Rankl, inhibited osteoclast differentiation in vitro and in vivo, and prevented the development of osteolytic lesions in a preclinical metastasis model. We conclude that pathological elevation of miR-218-5p in breast cancer cells activates Wnt signaling to enhance metastatic properties of breast cancer cells and cancer-induced osteolytic disease, suggesting that miR-218-5p could be an attractive therapeutic target for preventing disease progression.
authors.affiliation: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA.|Heisenberg-Group for Molecular Skeletal Biology, Department of Trauma, Hand & Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Taipaleenmäki
authors.affiliation: Department of Biochemistry & Cancer Center, University of Vermont College of Medicine, Burlington, VT, USA.
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Farina
authors.affiliation: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA.|Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA.
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.affiliation: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA.|Department of Biochemistry & Cancer Center, University of Vermont College of Medicine, Burlington, VT, USA.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stein
authors.affiliation: Heisenberg-Group for Molecular Skeletal Biology, Department of Trauma, Hand & Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Hesse
authors.affiliation: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA.|Department of Biochemistry & Cancer Center, University of Vermont College of Medicine, Burlington, VT, USA.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.affiliation: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA.|Department of Biochemistry & Cancer Center, University of Vermont College of Medicine, Burlington, VT, USA.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D001859:Bone Neoplasms / Q000235:genetics* / Q000556:secondary*; D045744:Cell Line, Tumor; D019295:Computational Biology; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009368:Neoplasm Transplantation; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000235:genetics*; D060449:Wnt Signaling Pathway; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D008565:Membrane Proteins; D035683:MicroRNAs; D044162:Parathyroid Hormone-Related Protein; D053245:RANK Ligand; C547471:MIRN218 microRNA, human; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins; C422903:SOST protein, human; C505688:TNFSF11 protein, human
keywords: Wnt signaling; breast cancer; metastasis; miR-218-5p; osteolysis