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dc.contributor.authorPratap, Jitesh
dc.contributor.authorWixted, John J.
dc.contributor.authorGaur, Tripti
dc.contributor.authorZaidi, Sayyed K.
dc.contributor.authorDobson, Jason
dc.contributor.authorGokul, Karthiga Devi
dc.contributor.authorHussain, Sadiq
dc.contributor.authorVan Wijnen, Andre J.
dc.contributor.authorStein, Janet L.
dc.contributor.authorStein, Gary S.
dc.contributor.authorLian, Jane B.
dc.date2022-08-11T08:08:04.000
dc.date.accessioned2022-08-23T15:41:11Z
dc.date.available2022-08-23T15:41:11Z
dc.date.issued2008-10-03
dc.date.submitted2008-12-22
dc.identifier.citationCancer Res. 2008 Oct 1;68(19):7795-802. <a href="http://dx.doi.org/10.1158/0008-5472.CAN-08-1078">Link to article on publisher's site</a>
dc.identifier.issn1538-7445 (Electronic)
dc.identifier.doi10.1158/0008-5472.CAN-08-1078
dc.identifier.pmid18829534
dc.identifier.urihttp://hdl.handle.net/20.500.14038/26575
dc.description.abstractRunx2, 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=18829534&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1158/0008-5472.CAN-08-1078
dc.subjectAnimals
dc.subjectBone Neoplasms
dc.subjectBreast Neoplasms
dc.subjectCore Binding Factor Alpha 1 Subunit
dc.subjectinhibitors
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectGenes, bcl-1
dc.subjectHedgehog Proteins
dc.subjectHumans
dc.subjectKruppel-Like Transcription Factors
dc.subjectMice
dc.subjectMice, SCID
dc.subjectModels, Biological
dc.subjectNuclear Proteins
dc.subjectOsteoclasts
dc.subjectParathyroid Hormone-Related Protein
dc.subjectRNA, Small Interfering
dc.subjectSignal Transduction
dc.subjectTissue Distribution
dc.subject*Transcriptional Activation
dc.subjectTransforming Growth Factor beta
dc.subjectTransplantation, Heterologous
dc.subjectTumor Cells, Cultured
dc.subjectCell Biology
dc.titleRunx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells
dc.typeJournal Article
dc.source.journaltitleCancer research
dc.source.volume68
dc.source.issue19
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/cellbiology_pp/81
dc.identifier.contextkey686326
html.description.abstract<p>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.</p>
dc.identifier.submissionpathcellbiology_pp/81
dc.contributor.departmentDepartment of Orthopedics and Physical Rehabilitation
dc.contributor.departmentDepartment of Cell Biology
dc.source.pages7795-802


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