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
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
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, 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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