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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA082834-06
Application #
7055052
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (O1))
Project Start
2006-02-01
Project End
2011-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
6
Fiscal Year
2006
Total Cost
$145,452
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Type
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Araya, H├ęctor F; Sepulveda, Hugo; Lizama, Carlos O et al. (2018) Expression of the ectodomain-releasing protease ADAM17 is directly regulated by the osteosarcoma and bone-related transcription factor RUNX2. J Cell Biochem 119:8204-8219
Carver, Gary E; Locknar, Sarah A; Weaver, Donald L et al. (2018) Real-time detection of breast cancer at the cellular level. J Cell Physiol :
Tracy, Kirsten M; Tye, Coralee E; Ghule, Prachi N et al. (2018) Mitotically-Associated lncRNA (MANCR) Affects Genomic Stability and Cell Division in Aggressive Breast Cancer. Mol Cancer Res 16:587-598
Zaidi, Sayyed K; Fritz, Andrew J; Tracy, Kirsten M et al. (2018) Nuclear organization mediates cancer-compromised genetic and epigenetic control. Adv Biol Regul 69:1-10
Hong, Deli; Fritz, Andrew J; Finstad, Kristiaan H et al. (2018) Suppression of Breast Cancer Stem Cells and Tumor Growth by the RUNX1 Transcription Factor. Mol Cancer Res 16:1952-1964
Zaidi, Sayyed K; Nickerson, Jeffrey A; Imbalzano, Anthony N et al. (2018) Mitotic Gene Bookmarking: An Epigenetic Program to Maintain Normal and Cancer Phenotypes. Mol Cancer Res 16:1617-1624
Hong, Deli; Fritz, Andrew J; Zaidi, Sayyed K et al. (2018) Epithelial-to-mesenchymal transition and cancer stem cells contribute to breast cancer heterogeneity. J Cell Physiol 233:9136-9144
Farina, Nicholas H; Zingiryan, Areg; Vrolijk, Michael A et al. (2018) Nanoparticle-based targeted cancer strategies for non-invasive prostate cancer intervention. J Cell Physiol 233:6408-6417
Tracy, Kirsten M; Tye, Coralee E; Page, Natalie A et al. (2018) Selective expression of long non-coding RNAs in a breast cancer cell progression model. J Cell Physiol 233:1291-1299
Hong, Deli; Fritz, Andrew J; Gordon, Jonathan A et al. (2018) RUNX1-dependent mechanisms in biological control and dysregulation in cancer. J Cell Physiol :

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