Runx2 (Cbfa1/AML3) is a master transcription factor that activates/represses target genes dependent onnuclear architecture. Runx2 functional activity requires the fidelity of a unique nuclear matrix targeting signal(NMTS) that organizes in subnuclear domains Runx2 complexes with co-regulatory proteins that includechromatin remodeling factors and mediators of ECM signal transduction pathways (e.g., IGF-1, integrin,TGF/BMP and c-Src) for expression of Runx2 target genes. Runx2 was discovered as essential for skeletalformation and regulates genes that control cell growth (p21), recruitment of blood vessels(VEGF),differentiation of mesenchymal lineage cells and expression of proteins for ECM formation and degradation(osteopontin, bone sialoprotein, matrix metalloproteinases). Recently, high Runx2 expression has beenreported in metastatic breast cancer cell lines (MDA-MB-231 and LCC15) that result in destructive osteolyticlesions in bone. Based on our findings that mutations in Runx2 which block Runx2 targeting functions andinhibit tumor progression and osteolysis in bone, we postulate that Runx2 controls expression of genesinducing metastatic properties associated with tumor progression and osteolysis in the bonemicfoenvironment.
Our specific aims are directed to understanding the mechanisms by which 1)endogenous Runx2 functions in metastatic breast cancer cells and 2) the subnuclear targeting deficientRunx2 mutant protein (STDmRunx2) inhibits expression of Runx2 target genes and blocks tumor growth andosteolysis in vivo. Using in vitro molecular and in vivo assays of human MDA-MB-231 metastatic breastcancer cells expressing WT and STDmutant Runx2 proteins, we will address: 1) the Runx2 response tosignaling pathways hyperactive in metastatic cells (with Project 1); 2) the role of Runx2 mediated histonemodifying (HDACs and HATs) and SWI/SNF chromatin remodeling factors in the control of target genes inbreast cancer cells (with Project 2); 3) the phenotype change induced by WT and STDmRunx2 proteins andthe in vivo fate of the cells lines (with Projects 1,2 and 3); and 4) a potential role of Runx2 in development ofprimary mammary tumors (with Project 2).Lay Summary: Metastatic breast carcinomas most frequently occur in bone. An estimated 70% morbidity ofpatients with metastatic breast cancer is associated with the destruction of bone that occurs when the tumorcells grow in bone. We have discovered that blocking a unique property of a master regulatory protein Runx2that activates genes highly expressed in metastatic cells, can prevent tumor growth and osteolytic lesions inbone. By addressing the mechanisms accounting for this remarkable effect, a potential therapeutic strategycan be developed to prevent this end-stage of breast cancer.
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