Androgen Regulation of Gene Expression, Transgenic Mouse Models for Prostate Cancer, and Gene Therapy
In North America, one in ten men is diagnosed with prostate cancer. Prostate cancer starts as an androgen dependent disease that progresses to an androgen independent cancer. The androgen independent tumors fail therapy. One of the major impediments to prostate cancer research is that no appropriate animal model system adequately displays the recognized stages of human prostatic disease. Further, no new therapeutic approaches have been developed after current therapy fails. Our laboratory has developed the probasin (PB) gene as a model system for androgen action, to establish new transgenic animal models for prostate cancer, and to test new therapeutic approaches for treatment.
The androgen receptor (AR) can function through similar cis-acting DNA elements similar to the palindromic glucocorticoid response element; however, recent data has shown that distinct AR elements (ARE) exist and function via cooperative interactions of multiple elements in the PB promoter. Further, since the PB promoter directs prostate specific expression in transgenic mice, it has become a model to dissect the key cis-acting DNA elements that control prostate-specific gene expression. Our laboratory has designed new PB promoters that target high levels of transgene expression to the prostate. These new promoters now serve to create new animal models for prostate cancer and to develop gene therapy vectors that will target a therapeutic gene(s) in the treatment of prostate cancer.
The PB promoter has been linked to oncogenes and growth factors to create new transgenic mouse models for prostate cancer. Transgenic mice carrying PB-oncogenes develop various stages of disease including prostatic precursor lesions that advance to an adenocarcinoma and then to high grade metastatic cancer. Gene expression profiles are being analyzed in these animal models to identify the key genes involved in tumor progression. By identifying the genes that are responsible for tumor progression, we can develop new targets for therapeutic intervention.