Antagonizing miR-218-5p attenuates Wnt signaling and reduces metastatic bone disease of triple negative breast cancer cells
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Hanna Taipaleenmäki1,2, Nicholas H. Farina3, Andre J. van Wijnen1,4, Janet L. Stein1,3, Eric Hesse2,5,*, Gary S. Stein1,3,*, Jane B. Lian1,3,*
1Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA
2Heisenberg-Group for Molecular Skeletal Biology, Department of Trauma, Hand & Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
3Department of Biochemistry & Cancer Center, University of Vermont College of Medicine, Burlington, VT, USA
4Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
5Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA
*These authors have contributed equally to this work
Jane B. Lian, email: firstname.lastname@example.org
Hanna Taipaleenmäki, email: email@example.com
Keywords: metastasis, breast cancer, osteolysis, Wnt signaling, miR-218-5p
Received: May 08, 2016 Accepted: September 19, 2016 Published: October 12, 2016
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.
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