Prostate cancer is the leading cause of male cancer-related deaths in the United States (about 32,000 this year) and the leading diagnosed cancer in American men (about 241,000 new cases in 2012). The number of new prostate cancer diagnoses has risen recently. These alarming statistics require special attention from clinicians, healthcare providers, scientific communities, and funding agencies. Different genetic changes have been identified to cause prostate cancer in men. One of the common mechanisms of tumor formation in cancer patients is inactivation of one or more so- called tumor suppressor genes. Inactivation of tumor suppressor genes has devastating consequences on the regulation of cell growth within a specific tissue and results in tumor development. Our group has identified one such tumor suppressor gene, Abi1/Hssh3bp1, and has developed a novel conditional knockout mouse model to study the role of this gene in development of prostate cancer. Prostate-specific disruption of the Abi1/Hssh3bp1 gene leads to development of prostatic intraepithelial neoplasia (PIN). Given our published data indicating that the observed prostate pathology in Abi1 KO mice is the result of abnormally regulated cell- to-cell adhesion and activation of PI-3 kinase-Akt pathway, this mouse model provides a much- needed mechanistically based animal model with which to conduct detailed studies of Abi1's tumor suppressive role as well as its role in the initiation of neoplastic processes leading to prostate cancer. Moreover, our preliminary data from additional mouse models generated in the lab indicate that Abi1 acts downstream from the most commonly mutated gene in prostate cancer, PTEN, and regulates tumor invasion. A better understanding of Abi1's function might lead to new therapeutic options for the treatment of prostate cancer and establishment of the novel mouse model for translational research in prostate cancer.

Public Health Relevance

Prostate cancer is the leading cause of cancer-related deaths in males in the United States and a leading diagnosed cancer in American men, with about 240,000 new cases in 2012. Here we propose to study mechanisms underlying prostate cancer by using a novel genetically engineered mouse model of prostate cancer produced in our laboratory. We hope that our research will lead to significant advancement of our basic knowledge, including identification of novel processes that lead to tumor formation and to identification of novel drug targets for cancer therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA161018-05
Application #
9313175
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Yassin, Rihab R
Project Start
2013-09-18
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2019-07-31
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Upstate Medical University
Department
Urology
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210
Nath, Disharee; White, Julie R; Bratslavsky, Gennady et al. (2018) Identification, Histological Characterization, and Dissection of Mouse Prostate Lobes for In Vitro 3D Spheroid Culture Models. J Vis Exp :
Colicino, Erica G; Garrastegui, Alice M; Freshour, Judy et al. (2018) Gravin regulates centrosome function through PLK1. Mol Biol Cell 29:532-541
Gleicher, Stephanie; Kauffman, Eric C; Kotula, Leszek et al. (2016) Implications of High Rates of Metastatic Prostate Cancer in BRCA2 Mutation Carriers. Prostate 76:1135-45
Kumar, Sushil; Lu, Bin; Dixit, Updesh et al. (2015) Reciprocal regulation of Abl kinase by Crk Y251 and Abi1 controls invasive phenotypes in glioblastoma. Oncotarget 6:37792-807
Sowalsky, Adam G; Sager, Rebecca; Schaefer, Rachel J et al. (2015) Loss of Wave1 gene defines a subtype of lethal prostate cancer. Oncotarget 6:12383-91
Vourganti, Srinivas; Donaldson, Jeffrey; Johnson, Linda et al. (2014) Defining the radiobiology of prostate cancer progression: An important question in translational prostate cancer research. Exp Biol Med (Maywood) 239:805-812