Runx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells
Department of Cell Biology; Department of Orthopedics and Physical Rehabilitation
Animals; Bone Neoplasms; Breast Neoplasms; Core Binding Factor Alpha 1 Subunit; inhibitors; Gene Expression Regulation, Neoplastic; Genes, bcl-1; Hedgehog Proteins; Humans; Kruppel-Like Transcription Factors; Mice; Mice, SCID; Models, Biological; Nuclear Proteins; Osteoclasts; Parathyroid Hormone-Related Protein; RNA, Small Interfering; Signal Transduction; Tissue Distribution; *Transcriptional Activation; Transforming Growth Factor beta; Transplantation, Heterologous; Tumor Cells, Cultured
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.
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Citation: Cancer Res. 2008 Oct 1;68(19):7795-802. Link to article on publisher's site
Pratap, Jitesh; Wixted, John J.; Gaur, Tripti; Zaidi, Sayyed K.; Dobson, Jason; Gokul, Karthiga Devi; Hussain, Sadiq; Van Wijnen, Andre J.; Stein, Janet L.; Stein, Gary S.; and Lian, Jane B., "Runx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells" (2008). Cell and Developmental Biology Publications. 81.