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Bone Abstracts (2016) 5 CABSOP2.1 | DOI: 10.1530/boneabs.5.CABS.OP2.1


1Heisenberg-Group for Molecular Skeletal Biology, Department of Trauma, Hand and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 2Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA; 3Department of Biochemistry and Vermont Cancer Center, University of Vermont College of Medicine, Burlington, Vermont, USA; 4Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, USA.

Signaling pathways crucial in bone development, including Wnt, are also upregulated in breast cancer cells to promote tumor growth in the skeleton, a process known as osteomimicry. Thus, we hypothesized that bone metastatic tumor cells also aberrantly express osteogenic miRNAs to support osteomimetic properties. We have previously shown that miR-218 is highly expressed in osteoblasts and promotes osteogenic differentiation. Interestingly, expression analysis revealed a significant up-regulation of miR-218 in bone metastatic MDA-MB-231 breast cancer cells compared to normal mammary epithelial cells. Furthermore, miR-218 was highly expressed in bone metastases biopsies from breast cancer patients, suggesting a positive role in bone metastasis. Indeed, delivery of miR-218 in MDA-MB-231-Luc cells promoted tumor growth in the bone microenvironment in vivo whereas inhibition of miR-218 impaired tumor growth. Signaling pathway analyses revealed a positive correlation between aberrant miR-218 expression and activation of Wnt signaling, demonstrated by reporter assays and expression of Wnt transcriptional mediators. Mechanistically, miR-218 targeted Wnt inhibitors Sclerostin and sFRP-2 and thus, delivery of miR-218 further enhanced while inhibition of miR-218 decreased Wnt activity. Importantly, the miR-218-induced expression of metastasis-related genes including bone sialoprotein, osteopontin and CXCR-4 was abolished by inhibition of Wnt signaling, indicating a Wnt-dependent regulation. Furthermore, PTHrP, a key cytokine promoting cancer-induced osteolysis was up-regulated in breast cancer cells by miR-218 in a Wnt-dependent manner. Consequently, conditioned medium from miR-218 expressing breast cancer cells increased Rankl in osteoblasts and supported osteoclast differentiation in osteoblast-osteoclast co-cultures. Importantly, antagonizing miR-218 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. In conclusion, we propose that miR-218 activates Wnt signaling to enhance metastatic properties of breast cancer cells and cancer-induced osteolytic disease. Therefore, antagonizing miR-218 represents a novel therapeutic intervention to prevent disease progression.

Volume 5

43rd Annual European Calcified Tissue Society Congress

Rome, Italy
14 May 2016 - 17 May 2016

European Calcified Tissue Society 

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