The transcription factor Egr1 (Early Growth Response Gene 1) has been implicated in diverse roles in the regulation of growth, apoptosis and differentiation. In some tumor types, such as lung cancers and gliomas, Egr1 is expressed at low levels, and its overexpression in these tumor cell lines is reported to result in growth suppression. In contrast, several independent studies have shown that Egr1 is overexpressed in prostate tumors and can promote prostate tumor progression. In prostate cancer-prone transgenic mice, lack of Egr1 significantly impairs tumor progression. We have recently observed a functional interaction between Egr1 and the androgen receptor (AR) in prostate carcinoma cells in culture. We therefore hypothesize that the effects of Egr1 on tumorigenesis are critically dependent on the cellular context, and that functional interactions between Egr1 and AR in prostate carcinoma cells contributes to the ability of Egr1 to specifically promote tumor progression in the prostate. To test these hypotheses, we propose the following Specific Aims: I. To determine the consequences of the interaction between Egr1 and AR in prostate carcinoma cells in culture by functional studies, and by target gene analysis. II. To generate and characterize transgenic mice that overexpress, Egr1 in the prostate. Ill. To analyze prostate tumorigenesis and response to castration in prostate cancer-prone animals that constitutively overexpress Egrl. These studies are likely to shed light on our understanding of tissue-specific mechanisms of tumor initiation, progression and maintenance in the prostate.
