Genetic variation in the androgen receptor impacts prostate cancer initiation and progression in the humanized AR mouse.

Abstract

Genetic variation of the androgen receptor (AR) impacts its function in male development and disease. The length of a polymorphic N-terminal glutamine (Q) tract (CAG repeat) correlates inversely with AR transcriptional strength and is implicated in prostate cancer risk. To investigate Q tract length effects, we converted the mouse AR to the human sequence by germline gene targeting, creating three humanized AR (h/mAR) alleles with 12, 21, or 48 Qs. H/mAR mice are physiologically normal, with similar global gene expression in the prostate as assessed by oligonucleotide microarray analysis. However, subtle differences were identified in some androgen-influenced traits and, by Q-PCR, in AR-regulated genes. Q tract effects on oncogenesis were examined by crossing h/mAR mice to TRAMP, a SV40 T antigen (Tag)-induced prostate cancer model. At 12 weeks, 12Q mice had more preneoplastic lesions (PIN), and while initial tumor palpation was similar for 12Q and 21Q mice. 12Q mice survived longer. Pathology and analysis of molecular markers together suggest the stronger 12Q-AR promotes earlier preneoplastic disease but slower progression of more differentiated tumors. PIN, tumor detection and death occurred latest in 48Q mice. When mice were castrated at 12 weeks to model androgen-independent disease, Q tract length had remarkably opposite effects than in intact mice, with delayed tumor detection and death in 12Q compared to 2IQ and 48Q animals. Further, Q tract length influenced response to androgen ablation, providing benefit to 12Q but more rapid disease in 48Q mice. The marked differences between genotypes in castrated mice emphasized AR's importance in androgen-independent as well as---dependent disease, and reveal a novel androgen-independent Q tract function. In addition to germline variation, AR somatic mutation may also impact prostate cancer, particularly in therapy resistance. Novel AR mutations identified from h/mAR-TRAMP tumors clustered in the N-terminal domain and in a region of the ligand binding domain. These mutations may alter AR function to enhance tumor cell survival. In sum, these studies demonstrate a dramatic effect of Q tract length prostate cancer initiation and progression. The h/mAR allelic series provides a useful model for studying mechanisms of androgen-independence and response to treatment.