Humanized Androgen Receptor Mice: A Genetic Model for Differential Response to Prostate Cancer Therapy
Annual rept. 15 Apr 2008-14 Apr 2009
MICHIGAN UNIV ANN ARBOR
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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 prostate tumors. This provides a genetic paradigm in which to dissect AR functions that determine response to therapy. 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 first year of this award, we have constructed the necessary mouse strains to generate experimental animals, using a modified approach for optimal tumorigenesis. In the in vitro studies, we have shown that AR Q tract length confers differential activation in a promoter- and cell type-dependent manner. In addition, ARs with different Q tract lengths are differentially responsive to signal transduction cascades likely to be influential under castrate conditions. Furthermore, phosphorylation of AR by growth factor activation correlates inversely with Q tract length, providing a potential mechanism by which this polymorphism impacts AR function in castration recurrent prostate cancer.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research