Abstract

The overall objective of this work is to enhance the understanding of prostate cancer initiation and progression. The main goal of the present proposal is to characterize new models of hormonal carcinogenesis in the mouse prostate. These experiments will use retinoblastoma (Rb) gene-knockout and conditionally deleted-Rb mouse prostate as a target for hormonal carcinogenesis. Experiments will examine the ontogeny and histopathology of carcinogenesis (aim 1), the precise role played by sex steroids (aim 2) and the specific epithelial cell type targeted by hormonal carcinogens (aim 3). A panel of cell strains will be derived from the tumors which are generated. Their behavior in vivo will be characterized and they will be subject to genomic analysis to identify common genetic lesions associated with prostate cancer (aim 4). Data from these studies will be used to identify candidate genes involved in prostatic carcinogenesis. The central hypothesis is that the progression from normal histology to cancer seen in mouse prostatic tissue lacking expression of the Rb tumor-suppressor gene is a good in vivo model of human prostate cancer. This project will use two new in vivo models of prostatic carcinogenesis. The first is a tissue recombination model based upon prostatic epithelium derived from the Rb-knockout mouse. The second model is a conditional deletion of Rb in the luminal epithelial cells of the prostate utilizing cre-lox technology. In both models a combination of testosterone and estradiol will be used to initiate the formation of prostate tumors. Prostate tumors will be used to generate a spectrum of cell lines representative of the stages from normal prostate to hormone- independent prostate cancer. These cell lines will serve as a source material to examine genomic lesions associated with prostate cancer progression. The following specific aims will be pursued.
Specific Aim 1 Characterization of tumor progression in Rb-deficient mouse prostate under the influence of testosterone and estradiol.
Specific Aim 2 An examination of the roles of testosterone and estradiol in hormonally induced prostatic carcinogenesis in the Rb-deficient mouse prostate Specific Aim 3 Generation and Characterization of ARR2Pb-cre RbloxP/loxP mice. Hormonal Carcinogenesis in ARR2Pb-cre RbloxP/loxP mice.
Specific Aim 4 Isolation, phenotypic and genomic characterization of Rb-deficient cell strains.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01CA096403-01
Application #
6492683
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Mohla, Suresh
Project Start
2001-09-25
Project End
2006-08-31
Budget Start
2001-09-25
Budget End
2002-08-31
Support Year
1
Fiscal Year
2001
Total Cost
$314,363
Indirect Cost

  Institution

Name
Vanderbilt University Medical Center
Department
Surgery
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212

  Publications

Ao, Mingfang; Franco, Omar E; Park, Dean et al. (2007) Cross-talk between paracrine-acting cytokine and chemokine pathways promotes malignancy in benign human prostatic epithelium. Cancer Res 67:4244-53
He, Yue; Franco, Omar E; Jiang, Ming et al. (2007) Tissue-specific consequences of cyclin D1 overexpression in prostate cancer progression. Cancer Res 67:8188-97
Ao, Mingfang; Williams, Karin; Bhowmick, Neil A et al. (2006) Transforming growth factor-beta promotes invasion in tumorigenic but not in nontumorigenic human prostatic epithelial cells. Cancer Res 66:8007-16
Ricke, William A; Ishii, Kenichiro; Ricke, Emily A et al. (2006) Steroid hormones stimulate human prostate cancer progression and metastasis. Int J Cancer 118:2123-31
Wang, Yongqing; Kasper, Susan; Yuan, Jialing et al. (2006) Androgen-dependent prostate epithelial cell selection by targeting ARR(2)PBneo to the LPB-Tag model of prostate cancer. Lab Invest 86:1074-88
Sun, Huifang; Chang, Yanjie; Schweers, Brett et al. (2006) An E2F binding-deficient Rb1 protein partially rescues developmental defects associated with Rb1 nullizygosity. Mol Cell Biol 26:1527-37
Williams, Karin; Fernandez, Suzanne; Stien, Xavier et al. (2005) Unopposed c-MYC expression in benign prostatic epithelium causes a cancer phenotype. Prostate 63:369-84
Ishii, Kenichiro; Shappell, Scott B; Matusik, Robert J et al. (2005) Use of tissue recombination to predict phenotypes of transgenic mouse models of prostate carcinoma. Lab Invest 85:1086-103
Davis, Joanne N; McCabe, Michael T; Hayward, Simon W et al. (2005) Disruption of Rb/E2F pathway results in increased cyclooxygenase-2 expression and activity in prostate epithelial cells. Cancer Res 65:3633-42
Gao, Nan; Ishii, Kenichiro; Mirosevich, Janni et al. (2005) Forkhead box A1 regulates prostate ductal morphogenesis and promotes epithelial cell maturation. Development 132:3431-43

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