Glutamine tract length of human androgen receptors affects hormone-dependent and -independent prostate cancer in mice

Abstract

The androgen receptor (AR) is involved in the initiation and progression of prostate cancer and its transition to androgen independence. Genetic variation in AR may contribute to disease risk and has been studied for a polymorphic N-terminal glutamine (Q) tract that shows population heterogeneity. While the length of this tract is known to affect AR in vitro, association with disease is complicated by genetic and environmental factors that have led to discordant epidemiological findings. To clarify the effect of Q tract polymorphism on prostate cancer, we created mice bearing humanized AR genes (h/mAr) varying in Q tract length. ARs with short Q tracts (12Q), which are transcriptionally more active, induce earlier disease in the transgene-induced TRAMP prostate cancer model than alleles with median (21Q) or long (48Q) tracts. Disease length varies within each genotype, with greater differentiation and AR expression in slower growing tumors. Remarkably, following androgen ablation, Q tract length has effects that are also allele-dependent and in directions opposite to those in hormone intact mice. Differences in AR activity conferred by Q tract length thus appear to direct distinct pathways of androgen-independent as well as androgen-dependent progression, and highlight substantial risk that may be associated with alterations in the androgen axis. This AR allelic series in humanized mice provides an experimental paradigm to dissect the role of AR in prostate cancer initiation and progression, to model response to treatment and to test therapies targeted specifically to the human AR.

Interaction of the Androgen Receptor, ETV1, and PTEN Pathways in Mouse Prostate Varies with Pathological Stage and Predicts Cancer Progression

“…Q-tract length inversely correlates with AR transcriptional activity in vitro , seen as altered prostatic gene expression and endpoints of androgen action such as seminal vesicle weight [4, 17, 65]. Previously, we showed that AR Q-tract length modifies PCa onset, progression and treatment response in the aggressive TRAMP mouse model [3]. Thus, variable AR transcriptional activity has the potential to modulate the effect of additional oncogenic events and alter the course of disease.…”

“…The antibodies used in this study included AR N-20 (Santa Cruz # sc-816, 1:500 dilution), phospho-AKT (Ser473) (Cell Signaling #9271, 1:100 dilution), and PTEN (Cell Signaling #9188, 1:80 dilution). Immunohistochemistry (IHC) was performed essentially as described for AR and pAKT [3], and for PTEN [61, 13]. …”

“…Q-tract length alone has not proven to be associated with PCa risk in humans but in combination with alleles of the androgen synthesis genes CYP17 and SRD5A2 the stronger AR increases PCa risk, supporting the notion that the androgen axis overall influences disease [44, 45]. We have previously shown that altering AR strength via Q-tract length variation on a homogenous genetic background modifies PCa onset and progression in an aggressive transgenic mouse model [3]. Interestingly, AR genetic variation has recently been reported to be associated with the frequency of recurrent gene fusions in PCa (see below) [82, 9].…”

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

“…The AR Q tract influence noted in mouse PCa (4) suggests differences in AR strength may contribute to differences in response to androgen ablation. Greater transcriptional activity of short Q tract ARs is due to greater interaction between AR's N and C terminus (N/C interaction), which leads to greater response at lower ligand levels and greater coactivator recruitment (9).…”

“…Upon activation of a prostate-targeted oncogene however distinct allele-dependent differences in disease progression are evident. These allelic differences also impact progression following androgen ablation (4). Mice with the more active AR12Q respond well to castration, whereas those with the weaker AR48Q show no benefit from treatment.…”