Two diseases of the prostatic epithelium, benign prostatic hyperplasia (BPH) and prostate cancer, are among the major health problems faced by American men. Deregulation of prostatic epithelial cell proliferation is a central event in both benign and malignant prostatic disease about The objective of this application is to determine the mechanism(s) by which insulin-like growth factor (IGF) and epithelial growth factor (EGF) regulate the growth of human prostate epithelial cells, with emphasis on interactions between the IGF receptor, EGF receptor and the androgen receptor (AR) networks. The hypothesis to be tested is that androgen-induced genes also inducible by IGF or EGF provide an alternate mechanism for control of prostate epithelial cell proliferation and behavor. We will use a novel, well characterized family of SV40TAg immortalized human prostate epithelial cells, both androgen receptor negative (M12AR-) and androgen receptor positive (M12AR+) to achieve these specific aims: (1) To identify key genes induced in common in androgen receptor positive Ml2 cells by both androgen (DHT) and IGF or EGF by applying cDNA microarray analysis; (2) To determine the mechanism(s) by which IGF and EGF regulate prostate cell growth in vitro and in vivo. Candidate genes will be either over expressed or reduced in expression in the appropriate cell line by transfection or introduction of morpholino antisense oligonucleotides or antisense constructs. Proliferation, apoptosis, and differentiation will be assessed in vitro and in vivo by orthotopic injection into athymic nude mice; (3) To determine the expression patterns of the IGF, EGF, and androgen regulated genes identified in Aim 1 among human benign and malignant prostatic tissues. Prostate tissue arrays will be prepared from 400 prostate cancers and screened by immunohistochemistry or in situ hybridization, to confirm expression and assess the frequency of expression of the genes evaluated in our experimental system. These studies will provide comprehensive and unique insights into the mechanisms by which peptide growth factors provide alternate pathways to control prostate epithelial cell proliferation in benign and malignant states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052683-07
Application #
6707560
Study Section
Special Emphasis Panel (ZRG1-OBM-2 (06))
Program Officer
Mullins, Christopher V
Project Start
1998-05-18
Project End
2005-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
7
Fiscal Year
2004
Total Cost
$230,010
Indirect Cost
Name
Virginia Commonwealth University
Department
Pathology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
York, Timothy P; Plymate, Stephen R; Nelson, Peter S et al. (2005) cDNA microarray analysis identifies genes induced in common by peptide growth factors and androgen in human prostate epithelial cells. Mol Carcinog 44:242-51
Wu, Jennifer D; Odman, Austin; Higgins, Lily M et al. (2005) In vivo effects of the human type I insulin-like growth factor receptor antibody A12 on androgen-dependent and androgen-independent xenograft human prostate tumors. Clin Cancer Res 11:3065-74
Wu, Jennifer D; Higgins, Lily M; Steinle, Alexander et al. (2004) Prevalent expression of the immunostimulatory MHC class I chain-related molecule is counteracted by shedding in prostate cancer. J Clin Invest 114:560-8
Huang, Dan; Liu, Xuhui; Plymate, Stephen R et al. (2004) Proteomic identification of 14-3-3 sigma as a common component of the androgen receptor and the epidermal growth factor receptor signaling pathways of the human prostate epithelial cell line M12. Oncogene 23:6881-9
Plymate, Stephen R; Tennant, Marie K; Culp, Stephen H et al. (2004) Androgen receptor (AR) expression in AR-negative prostate cancer cells results in differential effects of DHT and IGF-I on proliferation and AR activity between localized and metastatic tumors. Prostate 61:276-90
Ware, Joy L (2004) What can proteomic analyses contribute to understanding the molecular biology and clinical behavior of prostate cancer? Expert Rev Proteomics 1:485-92
Rubinstein, Moran; Idelman, Gila; Plymate, Stephen R et al. (2004) Transcriptional activation of the insulin-like growth factor I receptor gene by the Kruppel-like factor 6 (KLF6) tumor suppressor protein: potential interactions between KLF6 and p53. Endocrinology 145:3769-77
Wu, J; Haugk, K; Plymate, S R (2003) Activation of pro-apoptotic p38-MAPK pathway in the prostate cancer cell line M12 expressing a truncated IGF-IR. Horm Metab Res 35:751-7
Plymate, Stephen R; Haugk, Kathy H; Sprenger, Cynthia C et al. (2003) Increased manganese superoxide dismutase (SOD-2) is part of the mechanism for prostate tumor suppression by Mac25/insulin-like growth factor binding-protein-related protein-1. Oncogene 22:1024-34
Guo, Ning; Ye, Jing-Jing; Liang, Shu-Jian et al. (2003) The role of insulin-like growth factor-II in cancer growth and progression evidenced by the use of ribozymes and prostate cancer progression models. Growth Horm IGF Res 13:44-53

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