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 third year of this award, in in vitro studies, we showed that ARs with different Q tract lengths are differentially responsive to growth factor activation likely to be influential under castrate conditions. At least some of this differential activity appears to affected by phosphorylation at S-650. At this time, nearly all the experimental mice aged for tumorigenesis (containing a short or long Q-tract AR allele [12Q vs. 48Q], an ETV1 transgene and heterozygous loss of PTEN) have reached their time point and prostate samples have been collected for histology and biochemical analysis. Since tumorigenesis was much slower than anticipated, we performed some interim analysis on ETV1 transgenics wild type for PTEN to test AR efficacy. This will be an important control for the mice deficient in PTEN since both ETV1 and PTEN prove to directly influence AR action, which has relevance to human as well as mouse prostate cancer progression.