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
Zhang, Xuhui; Akech, Jacqueline; Browne, Gillian et al. (2015) Runx2-Smad signaling impacts the progression of tumor-induced bone disease. Int J Cancer 136:1321-32
Kapinas, Kristina; Kim, Heesun; Mandeville, Matthew et al. (2015) microRNA-mediated survivin control of pluripotency. J Cell Physiol 230:63-70
Gordon, Jonathan A R; Montecino, Martin A; Aqeilan, Rami I et al. (2014) Epigenetic pathways regulating bone homeostasis: potential targeting for intervention of skeletal disorders. Curr Osteoporos Rep 12:496-506
Barutcu, A Rasim; Tai, Phillip W L; Wu, Hai et al. (2014) The bone-specific Runx2-P1 promoter displays conserved three-dimensional chromatin structure with the syntenic Supt3h promoter. Nucleic Acids Res 42:10360-72
Stumpff, Jason; Ghule, Prachi N; Shimamura, Akiko et al. (2014) Spindle microtubule dysfunction and cancer predisposition. J Cell Physiol 229:1881-3
Zaidi, Sayyed K; Grandy, Rodrigo A; Lopez-Camacho, Cesar et al. (2014) Bookmarking target genes in mitosis: a shared epigenetic trait of phenotypic transcription factors and oncogenes? Cancer Res 74:420-5
Dutta, Anindita; Li, Jing; Lu, Huimin et al. (2014) Integrin ?v?6 promotes an osteolytic program in cancer cells by upregulating MMP2. Cancer Res 74:1598-608
Tai, Phillip W L; Zaidi, Sayyed K; Wu, Hai et al. (2014) The dynamic architectural and epigenetic nuclear landscape: developing the genomic almanac of biology and disease. J Cell Physiol 229:711-27
Tai, Phillip W L; Wu, Hai; Gordon, Jonathan A R et al. (2014) Epigenetic landscape during osteoblastogenesis defines a differentiation-dependent Runx2 promoter region. Gene 550:1-9
Lamba, Gurpreet; Zaidi, Sayyed Kaleem; Luebbers, Kimberly et al. (2014) Epigenetic landscape of acute myelogenous leukemia--moving toward personalized medicine. J Cell Biochem 115:1669-72

Showing the most recent 10 out of 132 publications