Two disease of prostatic epithelium, benign prostate 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. The objective of this proposal is to understand the role(s) of two tyrosine kinase growth factor families, their ligands and associated binding proteins, and the androgen receptor in control of human prostatic epithelial cell mitogenesis and differentiation. We use a well characterized family of SV40 T antigen- immortalized human prostate epithelial cells (PEC), as well as primary cultures of human prostatic epithelial cells, obtained from surgical specimens to achieve the following specific aims: (1) to determine the effects of insulin-like growth factor 1 (IGF-1) and epidermal growth factor (EGF) on proliferation of SV40 T immortalized human PEC lines. Growth factor responses will be studied individually and in combination of impact on cell growth and receptor mediated signal transduction. Functional significance will be tested by study of the effect of disruption on growth factor receptor function; (2) To construct androgen receptor positive sublines of these immortalized cell lines by transfection of a full length androgen receptor into these cells, to permit study of the impact of EGF and IGF on these cells, in the presence and absence of androgens; (3) To construct new immortalized PEC lines with an SV40 T antigen gene controlled by an inducible promoter. This will permit study of growth factor effects in the absence or presence of SV40 T antigen; and (4) To test the capacity of these cells for proliferation and/or differentiation within the prostate of the athymic nude mice. Investigation of the EGFR, IGFR, and androgen receptor systems as interactive networks is essential for development of effective new treatments for abnormal prostatic growth.
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