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. ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Snyderwine, Elizabeth G
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University of Pittsburgh
Biomedical Engineering
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United States
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Gau, David; Lewis, Taber; McDermott, Lee et al. (2018) Structure-based virtual screening identifies a small-molecule inhibitor of the profilin 1-actin interaction. J Biol Chem 293:2606-2616
Gau, David; Veon, William; Capasso, Teresa L et al. (2017) Pharmacological intervention of MKL/SRF signaling by CCG-1423 impedes endothelial cell migration and angiogenesis. Angiogenesis 20:663-672
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
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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

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