Runx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells
Authors
Pratap, JiteshWixted, John J.
Gaur, Tripti
Zaidi, Sayyed K.
Dobson, Jason
Gokul, Karthiga Devi
Hussain, Sadiq
Van Wijnen, Andre J.
Stein, Janet L.
Stein, Gary S.
Lian, Jane B.
UMass Chan Affiliations
Department of Orthopedics and Physical RehabilitationDepartment of Cell Biology
Document Type
Journal ArticlePublication Date
2008-10-03Keywords
AnimalsBone 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
Cell Biology
Metadata
Show full item recordAbstract
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.Source
Cancer Res. 2008 Oct 1;68(19):7795-802. Link to article on publisher's siteDOI
10.1158/0008-5472.CAN-08-1078Permanent Link to this Item
http://hdl.handle.net/20.500.14038/26575PubMed ID
18829534Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1158/0008-5472.CAN-08-1078