NUCLEAR ORGANIZATION OF TRANSCRIPTIONAL DOMAINS IN BREAST CANCER

Univ Of Massachusetts Med Sch Worcester, Worcester MA

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Abstract

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