The molecular targets contributing to PC progression are not well known and currently constitute a fundamental gap in the knowledge. The long-term goal is to understand the biological and molecular mechanisms governing PC metastasis. The objective of this application is to identify how the androgen induced pro-metastatic gene, CXCR4, contributes to PC progression via transactivation of epidermal growth factor receptor family members in PC cells. The central hypothesis is that androgens regulate CXCR4 expression via TMPRSS2-ERG activation and subsequent CXCR4 transactivation of growth factor receptors contributing to PC progression and metastasis. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Characterize the ERG transcription factor regulation of CXCR4 expression and determine the function of ERG isoforms on PC cells;2) We will investigate the Akt, MAPK and IKK kinase in ERG activation and subsequent CXCR4 expression in PC cells;and 3) Test the hypothesis that membrane microdomain located CXCR4 activation of Src and EGFR family members promotes PC progression.
The specific aims will be carried out using molecular biology and an in vivo orthotopic mouse model system. We will determine the effect of ERG and mutant ERG factors in CXCR4 regulation, and how the Akt pathway modulates ERG activation. Using a biochemical approach we will characterize the mechanism of CXCR4 transactivation of epidermal growth factor family members in lipid raft membrane microdomains. This approach is innovative, because the proposed project is designed to determine whether CXCR4 expression is a molecular link between TMPRSS2-ERG translocations and PC progression. Additionally, the novel CXCR4 transactivation of EGFR family members in lipid raft membrane microdomains will be determined at molecular level in PC cells. This proposed research is significant, because it is expected to advance and expand our understanding of how the frequent TMPRSS2-ERG translocations enhances the PC progression via upregulation of CXCR4 in transformed PC epithelial cells.

Public Health Relevance

TMPRSS2-ERG translocations are found in a subset of PC patients associated with an aggressive form of the disease. The consequences of TMPRSS2-ERG translocations are an under-investigated area in PC progression;therefore, defining the link between these translocations and CXCR4 activity may lead to the development of novel therapeutic strategies in these patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA151557-03
Application #
8265301
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Ault, Grace S
Project Start
2010-07-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$300,440
Indirect Cost
$99,165
Name
Wayne State University
Department
Urology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Wong, Donald; Kandagatla, Pridvi; Korz, Walter et al. (2014) Targeting CXCR4 with CTCE-9908 inhibits prostate tumor metastasis. BMC Urol 14:12
Conley-LaComb, M Katie; Saliganan, Allen; Kandagatla, Pridvi et al. (2013) PTEN loss mediated Akt activation promotes prostate tumor growth and metastasis via CXCL12/CXCR4 signaling. Mol Cancer 12:85
Singareddy, Rajareddy; Semaan, Louie; Conley-Lacomb, M Katie et al. (2013) Transcriptional regulation of CXCR4 in prostate cancer: significance of TMPRSS2-ERG fusions. Mol Cancer Res 11:1349-61