Abstract
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
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Bone Neoplasms / genetics*
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Bone Neoplasms / metabolism
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Bone Neoplasms / secondary*
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology*
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Core Binding Factor Alpha 1 Subunit / antagonists & inhibitors
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Core Binding Factor Alpha 1 Subunit / genetics
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Core Binding Factor Alpha 1 Subunit / metabolism
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Core Binding Factor Alpha 1 Subunit / physiology*
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Gene Expression Regulation, Neoplastic / drug effects
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Genes, bcl-1 / drug effects
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Hedgehog Proteins / genetics*
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Hedgehog Proteins / metabolism
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Humans
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Kruppel-Like Transcription Factors / metabolism
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Mice
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Mice, SCID
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Models, Biological
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Nuclear Proteins / metabolism
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Osteoclasts / drug effects
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Osteoclasts / metabolism
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Parathyroid Hormone-Related Protein / genetics
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Parathyroid Hormone-Related Protein / metabolism
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RNA, Small Interfering / pharmacology
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Signal Transduction / genetics
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Tissue Distribution
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Transcriptional Activation* / drug effects
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Transforming Growth Factor beta / pharmacology
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Transplantation, Heterologous
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Tumor Cells, Cultured
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Zinc Finger Protein Gli2
Substances
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Core Binding Factor Alpha 1 Subunit
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GLI2 protein, human
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Hedgehog Proteins
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Kruppel-Like Transcription Factors
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Nuclear Proteins
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Parathyroid Hormone-Related Protein
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RNA, Small Interfering
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RUNX2 protein, human
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Transforming Growth Factor beta
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Zinc Finger Protein Gli2