Human Molecular Genetics Advance Access originally published online on September 29, 2007
Human Molecular Genetics 2008 17(1):98-110; doi:10.1093/hmg/ddm287
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Glutamine tract length of human androgen receptors affects hormone-dependent and -independent prostate cancer in mice
1 Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109-0618, USA 2 University of Michigan Cancer Center Biostatistics Core, University of Michigan Medical School, Ann Arbor, MI 48109-0473, USA 3 Department of Urology, University of Michigan Medical School, Ann Arbor,MI 48109-0946, USA
* To whom correspondence should be addressed at: Department of Human Genetics, 4909 Buhl Bldg, University of Michigan Medical School, Ann Arbor, MI 48109-0618, USA. Tel: +1 7347644563; Fax: +1 7347633784; Email: drobins{at}umich.edu
Received August 8, 2007; Accepted September 27, 2007
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.
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