The master transcriptional regulator Runx2 is essential for osteogenesis and has multifunctional molecular and biological. Runx2 is properties as a scaffolding protein that interacts with distinct co-regulatory factors and is targeted by a unique Runx2 nuclear matrix targeting signal to subnuclear domains. Runx2 is highly expressed in tumor cells that metastasize to bone, present at trace levels in non-metastatic malignant cells and nearly absent from normal mammary epithelial cells. We have proven that the unique targeting function of Runx2 is an essential for its activity which promotes tumor growth in bone and osteolytic bone disease. We have shown that Runx2 is a transcriptional activator of many genes involved in early and late events of metastasis and mediates signaling pathways that contribute to tumor growth. Therefore, we hypothesize that Runx2 regulates a cohort of genes abnormally activated or repressed genes in highly metastatic breast cancer cells in subnuclear domains of tumor cells in mammary gland that will promote metastasis to distal sites. Importantly, we have established that loss of Runx2 fundion in tumor cells (by Runx2 shRNAs and a subnuclear targeting deficient (STD) mutation) reduces tumor growth in the mammary gland and blocks metastatic bone disease. Thus, we propose to further understand the mechanisms of Runx2 activities that are responsive to the mammary tumor microenvironment and are aberrantly associated with subnuclear foci in tumor cells.
Our aims are to 1- Establish that Runx2 promotes metastasis of breast cancer cells from primary mammary tumors and that disruption of Runx2 in nuclear microenvironments will decrease metastatic events in a genetic mouse model;2- Characterize the specific Runx2 subnudear-dependent functions that are required for tumor growth in the mammary fat pad and the bone microenvironment;and 3- Identify specific regulatory proteins in subnuclear domains of breast cancer cells that support to tumor growth and metastasis. These studies, in collaboration with Projects 1 and 2, will define Runx2 as a principal mediator of tumor growth and metastasis by identifying novel Runx2-dependent signaling pathways which function in nuclear microenvironments and contribute to progression of breast cancer.

Public Health Relevance

Runx2 is activated and increases with severity of disease in prostate and breast cancers patients. Inactivation of this master transcription factor that regulates many metastasis related genes, can prevent tumor growth in bone, a stage ofthe disease having a poor outcome for patients. By investigating the functional activities of Runx2 in subnuclear foci in mammary tumors, we will gain insight into novel mechanisms operative during tumor progression and in promoting metastasis to distal sites

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA082834-15
Application #
8444560
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
15
Fiscal Year
2014
Total Cost
$184,681
Indirect Cost
$49,111
Name
University of Vermont State Agr Coll
Department
Type
DUNS #
City
Burlington
State
VT
Country
United States
Zip Code
Barutcu, A Rasim; Hong, Deli; Lajoie, Bryan R et al. (2016) RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells. Biochim Biophys Acta 1859:1389-1397
Varela, Nelson; Aranguiz, Alejandra; Lizama, Carlos et al. (2016) Mitotic Inheritance of mRNA Facilitates Translational Activation of the Osteogenic-Lineage Commitment Factor Runx2 in Progeny of Osteoblastic Cells. J Cell Physiol 231:1001-14
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Barutcu, A Rasim; Lajoie, Bryan R; Fritz, Andrew J et al. (2016) SMARCA4 regulates gene expression and higher-order chromatin structure in proliferating mammary epithelial cells. Genome Res 26:1188-201
VanOudenhove, Jennifer J; Medina, Ricardo; Ghule, Prachi N et al. (2016) Transient RUNX1 Expression during Early Mesendodermal Differentiation of hESCs Promotes Epithelial to Mesenchymal Transition through TGFB2 Signaling. Stem Cell Reports 7:884-896
Wu, Qiong; Madany, Pasil; Dobson, Jason R et al. (2016) The BRG1 chromatin remodeling enzyme links cancer cell metabolism and proliferation. Oncotarget 7:38270-38281
Taipaleenmäki, Hanna; Farina, Nicholas H; van Wijnen, Andre J et al. (2016) Antagonizing miR-218-5p attenuates Wnt signaling and reduces metastatic bone disease of triple negative breast cancer cells. Oncotarget :
VanOudenhove, Jennifer J; Grandy, Rodrigo A; Ghule, Prachi N et al. (2016) Unique Regulatory Mechanisms for the Human Embryonic Stem Cell Cycle. J Cell Physiol :
Barutcu, A Rasim; Fritz, Andrew J; Zaidi, Sayyed K et al. (2016) C-ing the Genome: A Compendium of Chromosome Conformation Capture Methods to Study Higher-Order Chromatin Organization. J Cell Physiol 231:31-5
Wu, Qiong; Sharma, Soni; Cui, Hang et al. (2016) Targeting the chromatin remodeling enzyme BRG1 increases the efficacy of chemotherapy drugs in breast cancer cells. Oncotarget 7:27158-75

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