Prostate cancer (PCa) is a major source of cancer morbidity and mortality in men. Androgen-deprivation, the main therapeutic intervention for advanced PCa patients, inevitably fails and the disease subsequently recurs in a hormone-refractory form that often leads to the death of the patient. Our goal of identifying novel molecular mechanisms through which PCa cells develop resistance to hormone therapy has led to the discovery of a unique gene product referred to as protocadherin-PC (PCDH-PC) that is upregulated in apoptosis- and hormone-resistant prostate cancer cells as well as in actual hormone-resistant tumors from patients. PCDH-PC is remarkable because of its male-specific nature (it is encoded on the human Y- chromosome) and because its expression is associated with activation of wnt- and Akt- signaling pathways as well as with the activation of a transdifferentiation process in which PCa cells acquire neuroendocrine (NE) cell-like characteristics. These behaviors (wnt-/Akt-signaling and NE phenotype) are found in advanced and hormone-resistant PCa cells and the work in this project will increase our understanding of PCDH-PC's role in hormone-resistant PCa. Experiments in Specific Aim 1 will explore the mechanism through which PCDH-PC upregulates wnt signaling by characterizing the domains of PCDH-PC that are involved in wnt signaling control. Experiments in Specific Aim 2 will characterize the effects of PCDH-PC expression on gene expression patterns in PCa cells and determine how PCDH-PC expression influences their malignant behavior. Work under Specific Aim 3 will develop a transgenic mouse model in which PCDH-PC expression is targeted to the prostate to determine whether expression of this gene product is sufficient to induce prostatic neoplasia or whether co-expression of this gene in existing transgenic prostate cancer models (LADY 12T-7 or PTEN knockout) leads to the development of more aggressive prostate cancers. By defining the mechanism through which PCDH-PC exerts its effects on the PCa cell and characterizing the malignant behaviors that are elicited by PCDH-PC expression, we will show the importance of this gene product for prostate cancer progression and better define it as a target for the development of therapeutics to control hormone-refractory disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA111618-01A2
Application #
7105762
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Woodhouse, Elizabeth
Project Start
2006-04-01
Project End
2006-07-31
Budget Start
2006-04-01
Budget End
2006-07-31
Support Year
1
Fiscal Year
2006
Total Cost
$55,043
Indirect Cost
Name
Columbia University (N.Y.)
Department
Urology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Chen, Mengqian; Carkner, Richard; Buttyan, Ralph (2011) The hedgehog/Gli signaling paradigm in prostate cancer. Expert Rev Endocrinol Metab 6:453-467
Chen, Mengqian; Tanner, Matthew; Levine, Alice C et al. (2009) Androgenic regulation of hedgehog signaling pathway components in prostate cancer cells. Cell Cycle 8:149-57
Yang, X; Chen, M-W; Terry, S et al. (2006) Complex regulation of human androgen receptor expression by Wnt signaling in prostate cancer cells. Oncogene 25:3436-44
Terry, Stephane; Queires, Luis; Gil-Diez-de-Medina, Sixtina et al. (2006) Protocadherin-PC promotes androgen-independent prostate cancer cell growth. Prostate 66:1100-13