MOUSE MODELS FOR PROSTATE CARCINOGENESIS

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Carcinoma of the prostate is the most prevalent cancer in males in the United States and represents a major public health concern. The molecular events underlying the initiation and progression of prostate carcinogenesis are unknown. We propose that the p53 and retinoblastoma (Rb) tumor suppressor genes are two pivotal genetic targets in prostate neoplastic development. In addition, we propose that the course of neoplastic development is also governed by the synergistic effects of specific activated oncogenes and the tumor suppressor gene functions. In the following Specific Aims we will use a novel animal model system to address the roles of p53, Rb, and other genes in the multistep process of prostate carcinogenesis by: (i) characterization and optimization of the C3(1)-based prostate expression vector for the targeted expression of transgenes in the prostate gland, (ii) construction of transgenic mouse lines that express genes implicated in human prostate cancer, or genes known to directly affect the function of these genes, (iii) analysis of the effects of the transgenes on prostate growth and development, and (iv) development of a binary transgenic system for androgen-regulated expression of transgenes. The experimental methodology builds on our successful design and implementation of an expression vector based on the well-characterized rat C3(1) steroid binding protein gene. Transgenic mouse lines have been generated with the Beta-galactosidase (Beta-gal) and the human papillomavirus type 16 E6 and E7 genes under transcriptional control of the C3(1) regulatory elements. The C3(1) gene was chosen as the basis for our expression vector system because transcription of the gene is restricted to the ventral lobe of the prostate. This proposal outlines a set of innovative approaches using transgenic mouse technologies to address the roles of specific cellular genes in the pathogenesis of prostate neoplasia. The long term objectives of this proposal are to identify additional genes involved in the initiation, progression, and metastasis of prostate cancer and to design strategies and therapies for the detection and treatment of this disease.