The overall goal of the proposed project is to investigate the functional significance of profilin-1 (Pfn1 - a cytoskeleton regulatory protein) downregulation in breast cancer. We will study how Pfn1, a traditionally pro- migratory molecule, can also regulate intracellular signaling generated at the membrane-cytosol interface to suppress breast cancer invasion and metastasis.
In Aim 1, we will first combine clinical correlation and mouse model studies to determine whether a) there is a casual relationship between Pfn1 dysregulation and metastatic progression of breast cancer, and b) Pfn1 expression reflects stages in tumor progression and predicts clinical outcome of breast cancer patients (Aim 1).
In Aims 2 and 3, we will identify the molecular pathways by which Pfn1 inhibits breast cancer dissemination Successful completion of these studies will determine whether Pfn1 could be used as a prognostic marker in breast cancer and justify novel cancer therapeutics revolving around Pfn1.

Public Health Relevance

Breast cancer ranks second among cancer deaths in women in the United States. In this project, we examine a novel mechanism of how profilin-1, a traditional pro-migratory cytoskeletal protein, regulates signaling at the membrane-cytosol interface and suppresses breast cancer invasion and metastasis. A successful completion of this study will yield novel insights into fundamental tumor cell biology and provide molecular underpinnings of basic adenocarcinoma behaviors that lead to progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA108607-06A1
Application #
8295389
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Snyderwine, Elizabeth G
Project Start
2004-07-01
Project End
2017-03-31
Budget Start
2012-05-01
Budget End
2013-03-31
Support Year
6
Fiscal Year
2012
Total Cost
$258,797
Indirect Cost
$81,793
Name
University of Pittsburgh
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Coumans, J V F; Gau, D; Poljak, A et al. (2014) Green fluorescent protein expression triggers proteome changes in breast cancer cells. Exp Cell Res 320:33-45
Ding, Z; Joy, M; Bhargava, R et al. (2014) Profilin-1 downregulation has contrasting effects on early vs late steps of breast cancer metastasis. Oncogene 33:2065-74
Joy, Marion E; Vollmer, Laura L; Hulkower, Keren et al. (2014) A high-content, multiplexed screen in human breast cancer cells identifies profilin-1 inducers with anti-migratory activities. PLoS One 9:e88350
Gau, Dave; Ding, Zhijie; Baty, Catherine et al. (2011) Fluorescence Resonance Energy Transfer (FRET)-based Detection of Profilin-VASP Interaction. Cell Mol Bioeng 4:1-8
Zou, Li; Ding, Zhijie; Roy, Partha (2010) Profilin-1 overexpression inhibits proliferation of MDA-MB-231 breast cancer cells partly through p27kip1 upregulation. J Cell Physiol 223:623-9
Das, Tuhin; Bae, Yong Ho; Wells, Alan et al. (2009) Profilin-1 overexpression upregulates PTEN and suppresses AKT activation in breast cancer cells. J Cell Physiol 218:436-43
Zou, Li; Hazan, Rachel; Roy, Partha (2009) Profilin-1 overexpression restores adherens junctions in MDA-MB-231 breast cancer cells in R-cadherin-dependent manner. Cell Motil Cytoskeleton 66:1048-56
Ding, Zhijie; Gau, David; Deasy, Bridget et al. (2009) Both actin and polyproline interactions of profilin-1 are required for migration, invasion and capillary morphogenesis of vascular endothelial cells. Exp Cell Res 315:2963-73
Bae, Yong Ho; Ding, Zhijie; Zou, Li et al. (2009) Loss of profilin-1 expression enhances breast cancer cell motility by Ena/VASP proteins. J Cell Physiol 219:354-64
Zou, L; Jaramillo, M; Whaley, D et al. (2007) Profilin-1 is a negative regulator of mammary carcinoma aggressiveness. Br J Cancer 97:1361-71

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