Prostate cancer is an age-dependent disease. There is currently no treatment that can prevent the development and/or progression of this deadly disease. Most of the work to date has focused on the advanced stages of prostate cancer. Very little work has been directed toward the prevention of prostate cancer during the early stages of this disease. A large number of epidemiological studies have suggested that phytoestrogens in soybean can reduce the risk for acquisition of hormone-dependent cancers. Several studies have demonstrated that genistein, the most abundant isoflavone present in soy, is responsible for this beneficial outcome. TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice develop age-dependent progressive forms of prostatic disease that histologically resemble human prostate cancer. Therefore, using the TRAMP model, we propose to investigate the effects of genistein on age-dependent and stage-specific development of prostatic carcinoma and establish the molecular mechanism(s) of growth inhibition.
The specific aims of this proposal are: First, we will determine the effects of genistein on the age-dependent development and progression of prostate cancer in TRAMP mice. To do so, TRAMP mice, before developing tumors, and mice bearing different stages of prostate cancer, will be treated with genistein for different time periods. Prostatic histopathology, cell proliferation and cell death will be examined in untreated vs. genistein-treated groups. Second, we will examine possible mechanisms by which genistein inhibits cell proliferation of prostate cancer in TRAMP mice in vivo, and in TRAMP cell lines (C1 and C2) in vitro. Specifically, we will investigate the effects of genistein on growth factor (TGF-alpha and/or IGF-I)-induced expression of cell cycle regulatory proteins and MAPK and PI3K pathways in TRAMP cell lines and in TRAMP dorsolateral prostate. Third., to examine the mechanisms of genistein-induced cell death, alterations in cell survival factors, pro-apoptotic and anti-apoptotic proteins and activation of caspase pathways will be evaluated in TRAMP dorsolateral prostate and/or TRAMP cell lines. This project will demonstrate the efficacy of genistein in early prevention of prostate cancer, and the mechanism of action underlying the prostate cancer suppressing activity of genistein. This information will lead to more effective prostate cancer prevention and control strategies in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060875-03
Application #
6947850
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Rankin, Tracy L
Project Start
2003-09-20
Project End
2008-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
3
Fiscal Year
2005
Total Cost
$288,284
Indirect Cost
Name
Georgetown University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
El Touny, Lara H; Banerjee, Partha P (2009) Identification of a biphasic role for genistein in the regulation of prostate cancer growth and metastasis. Cancer Res 69:3695-703
Banerjee, Partha P; Jagadeesh, Shankar (2009) Non-radioactive assay methods for the assessment of telomerase activity and telomere length. Methods Mol Biol 523:383-94
Chau, My N; Banerjee, Partha P (2008) Development of a STAT3 reporter prostate cancer cell line for high throughput screening of STAT3 activators and inhibitors. Biochem Biophys Res Commun 377:627-31
El Touny, Lara H; Banerjee, Partha P (2007) Genistein induces the metastasis suppressor kangai-1 which mediates its anti-invasive effects in TRAMP cancer cells. Biochem Biophys Res Commun 361:169-75
Chau, My N; El Touny, Lara H; Jagadeesh, Shankar et al. (2007) Physiologically achievable concentrations of genistein enhance telomerase activity in prostate cancer cells via the activation of STAT3. Carcinogenesis 28:2282-90
El Touny, Lara H; Banerjee, Partha P (2007) Akt GSK-3 pathway as a target in genistein-induced inhibition of TRAMP prostate cancer progression toward a poorly differentiated phenotype. Carcinogenesis 28:1710-7
Jagadeesh, Shankar; Kyo, Satoru; Banerjee, Partha P (2006) Genistein represses telomerase activity via both transcriptional and posttranslational mechanisms in human prostate cancer cells. Cancer Res 66:2107-15
Touny, Lara H El; Banerjee, Partha P (2006) Identification of both Myt-1 and Wee-1 as necessary mediators of the p21-independent inactivation of the cdc-2/cyclin B1 complex and growth inhibition of TRAMP cancer cells by genistein. Prostate 66:1542-55
Jagadeesh, Shankar; Banerjee, Partha P (2006) Telomerase reverse transcriptase regulates the expression of a key cell cycle regulator, cyclin D1. Biochem Biophys Res Commun 347:774-80