Humanized Androgen Receptor Mice: A Genetic Model for Differential Response to Prostate Cancer Therapy
Final rept. 15 Apr 2008-14 Apr 2012
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 of prostate tumors in the TRAMP mouse model. This provides a genetic paradigm in which to dissect AR functions that determine response to treatment. We developed a mouse model that more accurately reflects human disease, utilizing ETV1 overexpression and heterozygosity for PTEN loss, coupled with variation of the androgen axis via AR alleles differing in Q tract length. In vitro, Q tract length was shown to influence ligand-independent AR activation shorter Q tract lengths led to greater phosphorylation of a site in the AR hinge region, enhancing both transactivation and nuclear shuttling of the receptor. The new tumor model proved milder than expected, with a lethal phenotype occurring only at late age in a subset of mice, perhaps similar to PCa occurrence in man. Gene expression profiles in this model showed effects of ETV1 prior to any notable pathophysiology, supporting the notion of ETV1 overexpression as an early oncogenic event. The expression patterns revealed a strong antagonism between AR and ETV1 for a subset of AR target genes, and this antagonism was abrogated in a background of PTEN loss. Antagonism at the molecular level may lead to synergy at the disease level and may be subject to variation in AR allelic strength and androgen levels. Further knowledge of these variables may lead to better predictors for response to androgen ablation therapy.
- Anatomy and Physiology
- Medicine and Medical Research