This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pratap, J. Articles by Lian, J. B. Search for Related Content PubMed PubMed Citation Articles by Pratap, J. Articles by Lian, J. B.

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]