Breast cancer mortality is due to metastatic involvement of distant organs driven in large part by increased invasiveness. Previous studies show downregulation in the expression of profilin (an actin-binding protein which also has a tumor-suppressive effect) in metastatic breast cancer cells. This, taken together with our preliminary data showing that overexpressing profilin or it's mutants that are selectively impaired in binding to either actin or proline-rich motif (PRM) proteins significantly decreases the migration of breast carcinoma cells, leads to a hypothesis that profilin's function regulates breast cancer invasion and metastasis (HYPOTHESIS). The overall goal of the project is determine how perturbations of profilin can be utilized to suppress breast cancer invasion and metastasis. To test the hypothesis, in Aim I, we will first use a series of molecular constructs to determine how modulations of profilin's function alter the migration of breast cancer cells. Next, in order to determine the molecular basis for profilin-dependent changes in cell migration, we will investigate how various perturbations of profilin alter the cytoskeletal structure and the protrusive ability of cells.
In Aim II, we will first employ photomanipulative techniques to determine whether profilin's function is spatially restricted in migrating cells. Next, we will abolish profilin's interaction selectively with different classes of PRM proteins to identify the key PRM interactions in breast cancer cell migration, and then use fluorescence resonance energy transfer (FRET) technique to study the spatiotemporal aspects of these interactions during cell migration.
In Aim III, we will first determine how perturbations of profiin alter breast cancer cell invasion in an in vitro milieu partially mimicking tumor cell-stromal interactions. Finally, using animal model we will test whether perturbations of profilin are effective in inhibiting breast cancer metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA108607-05
Application #
7841847
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Snyderwine, Elizabeth G
Project Start
2006-07-12
Project End
2012-04-30
Budget Start
2010-06-01
Budget End
2012-04-30
Support Year
5
Fiscal Year
2010
Total Cost
$248,922
Indirect Cost
Name
University of Pittsburgh
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Joy, Marion; Gau, David; Castellucci, Nevin et al. (2017) The myocardin-related transcription factor MKL co-regulates the cellular levels of two profilin isoforms. J Biol Chem 292:11777-11791
Ding, Zhijie; Joy, Marion; Kameneva, Marina V et al. (2017) Nanomolar concentration of blood-soluble drag-reducing polymer inhibits experimental metastasis of human breast cancer cells. Breast Cancer (Dove Med Press) 9:61-65
Jiang, Chang; Ding, Zhijie; Joy, Marion et al. (2017) A balanced level of profilin-1 promotes stemness and tumor-initiating potential of breast cancer cells. Cell Cycle 16:2366-2373
Gau, David; Veon, William; Zeng, Xuemei et al. (2016) Threonine 89 Is an Important Residue of Profilin-1 That Is Phosphorylatable by Protein Kinase A. PLoS One 11:e0156313
Jiang, Chang; Veon, William; Li, Hui et al. (2015) Epithelial morphological reversion drives Profilin-1-induced elevation of p27(kip1) in mesenchymal triple-negative human breast cancer cells through AMP-activated protein kinase activation. Cell Cycle 14:2914-23
Valenzuela-Iglesias, A; Sharma, V P; Beaty, B T et al. (2015) Profilin1 regulates invadopodium maturation in human breast cancer cells. Eur J Cell Biol 94:78-89
Gau, David M; Lesnock, Jamie L; Hood, Brian L et al. (2015) BRCA1 deficiency in ovarian cancer is associated with alteration in expression of several key regulators of cell motility - A proteomics study. Cell Cycle 14:1884-92
Coumans, Joƫlle V F; Gau, David; Poljak, Anne et al. (2014) Profilin-1 overexpression in MDA-MB-231 breast cancer cells is associated with alterations in proteomics biomarkers of cell proliferation, survival, and motility as revealed by global proteomics analyses. OMICS 18:778-91
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
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

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