We seek to understand molecular regulatory mechanisms controlling breast tissue development and mammary epithelial cell transformation. SWI/SNF chromatin remodeling enzymes control the accessibility of genomic chromatin and are vitally important in the initiation of multiple differentiation programmes through regulation of cell cycle progression and gene expression. These enzymes interact with tumor suppressors, and individual subunits are tumor suppressors themselves. Our studies indicate that SWI/SNF enzymes can modulate gene expression, nuclear and cellular morphology, proliferation, and tissue development in mammary epithelial cells. We also showed that knockdown of one ofthe SWI/SNF ATPase subunits results in altered nuclear shape, identifying SWI/SNF enzymes as one of the few known nudear regulatory proteins that has a role in nuclear structure. The Runx2 transcriptional regulator is expressed at elevated levels in some breast and other cancer cells. We and other P01 investigators demonstrated that RUNX2 functions as an oncogene by promoting early stages of mammary epithelial cell transformation in a manner entirely dependent on proper subnuclear localization. We propose to mechanistically address how SWI/SNF enzymes and RUNX2 promote changes in nuclear and cellular architecture that lead to cancer. Since development and malignant transformation take place in a three dimensional context, we are utilizing model systems of normal and transformed breast cells that recapitulate the microenvironment of a tissue and that permit the dynamic and reciprocal crosstalk between the extracellular matrix and nuclear gene expression. In this application, wewill investigate the physiological functions for SWI/SNF enzymes in immortalized, transformed, and metastatic mammary epithelial cells in monolayer and in three dimensional, reconstituted basement membrane culture (Aim 1). We will further probe the role ofthese enzymes in maintaining nuclear shape by exploring how loss of the factors affects various parameters of nuclear structure (Aim 2).
In Aim 3, we will continue studies of RUNX2 function in mammary epithelial cell oncogenesis and will explore how SWI/SNF and RUNX2 factors may cooperate to promote cell transformation.

Public Health Relevance

A hallmark of many cancers is the altered morphological and functional state ofthe cell nucleus. We have shown that key regulatory factors known to affect parameters of nuclear structure modulate cellular properties associated with mammary epithelial cell transfomation. We seek to understand the molecular basis for these observations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA082834-15
Application #
8444559
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
$233,211
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
Zaidi, Sayyed K; Boyd, Joseph R; Grandy, Rodrigo A et al. (2016) Expression of Ribosomal RNA and Protein Genes in Human Embryonic Stem Cells Is Associated With the Activating H3K4me3 Histone Mark. J Cell Physiol 231:2007-13
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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