Humanized Androgen Receptor Mice: A Genetic Model for Differential Response to Prostate Cancer Therapy

In mice in which human androgen receptor (AR) replaces the endogenous murine gene, variation in the length of a polymorphic N-terminal polyglutamine tract affects initiation, progression and therapy response of prostate tumors. This provides a genetic paradigm in which to dissect AR functions that determine response to treatment. We are studying the role of the AR Q tract in ligand-independent AR activation in vitro and in a mouse model with prostate cancer ontogeny similar to human. In the mouse model, molecular correlates of differential response to castration will be determined using bioinformatic analysis of microdissected tumor samples. In the second year of this award, we have accrued the experimental mice from the strains constructed last year, using a modified genetic strategy thought to optimize similarity to human tumorigenesis. In the in vitro studies, we showed that ARs with different Q tract lengths are differentially responsive to signal transduction cascades likely to be influential under castrate conditions. We have tested several different pathways of such ligandindependent activation for their sensitivity to Q tract length. A phosphorylation site in the AR hinge region was examined by mutagenesis for a role in mechanisms underlying Q tract effects. Finally, we have begun to characterize differential prostate pathology in the mouse model as some animals have reached their designated end points.