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Runx2 Transcriptional Activation of Indian Hedgehog and a Downstream Bone Metastatic Pathway in Breast Cancer Cells

Departments of ¹ Cell Biology and Cancer Center and ² Orthopedic Surgery, University of Massachusetts Medical School, Worcester, Massachusetts

Requests for reprints: Jane B. Lian, Department of Cell Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655. Phone: 508-856-5625; Fax: 508-856-6800; E-mail: Jane.Lian{at}umassmed.edu.

Key Words: Runx2 • Bone Metastasis • Breast Cancer • PTHrP • TGFβ • Vicious cycle • shRNA-Runx2 • MDA-MB-231

Runx2, required for bone formation, is ectopically expressed in breast cancer cells. To address the mechanism by which Runx2 contributes to the osteolytic disease induced by MDA-MB-231 cells, we investigated the effect of Runx2 on key components of the "vicious cycle" of transforming growth factor β (TGFβ)-mediated tumor growth and osteolysis. We find that Runx2 directly up-regulates Indian Hedgehog (IHH) and colocalizes with Gli2, a Hedgehog signaling molecule. These events further activate parathyroid hormone-related protein (PTHrP). Furthermore, Runx2 directly regulates the TGFβ-induced PTHrP levels. A subnuclear targeting deficient mutant Runx2, which disrupts TGFβ-induced Runx2-Smad interactions, failed to induce IHH and downstream events. In addition, Runx2 knockdown in MDA-MB-231 inhibited IHH and PTHrP expression in the presence of TGFβ. In vivo blockade of the Runx2-IHH pathway in MDA-MB-231 cells by Runx2 short hairpin RNA inhibition prevented the osteolytic disease. Thus, our studies define a novel role of Runx2 in up-regulating the vicious cycle of metastatic bone disease, in addition to Runx2 regulation of genes related to progression of tumor metastasis. [Cancer Res 2008;68(19):7795–802]

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