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.
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