Runx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells

Cancer Res. 2008 Oct 1;68(19):7795-802. doi: 10.1158/0008-5472.CAN-08-1078.


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 beta (TGFbeta)-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 TGFbeta-induced PTHrP levels. A subnuclear targeting deficient mutant Runx2, which disrupts TGFbeta-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 TGFbeta. 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bone Neoplasms / genetics*
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / secondary*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Core Binding Factor Alpha 1 Subunit / antagonists & inhibitors
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Core Binding Factor Alpha 1 Subunit / physiology*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, bcl-1 / drug effects
  • Hedgehog Proteins / genetics*
  • Hedgehog Proteins / metabolism
  • Humans
  • Kruppel-Like Transcription Factors / metabolism
  • Mice
  • Mice, SCID
  • Models, Biological
  • Nuclear Proteins / metabolism
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism
  • Parathyroid Hormone-Related Protein / genetics
  • Parathyroid Hormone-Related Protein / metabolism
  • RNA, Small Interfering / pharmacology
  • Signal Transduction / genetics
  • Tissue Distribution
  • Transcriptional Activation* / drug effects
  • Transforming Growth Factor beta / pharmacology
  • Transplantation, Heterologous
  • Tumor Cells, Cultured
  • Zinc Finger Protein Gli2


  • Core Binding Factor Alpha 1 Subunit
  • GLI2 protein, human
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Nuclear Proteins
  • Parathyroid Hormone-Related Protein
  • RNA, Small Interfering
  • RUNX2 protein, human
  • Transforming Growth Factor beta
  • Zinc Finger Protein Gli2