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The Role of the Androgen Receptor Polyglutamine Tract in Prostate Cancer: In Mice and Men

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Androgen Action in Prostate Cancer

Abstract

The androgen receptor (AR) is critical in the initiation and progression of prostate cancer, and therefore may contribute to disease through its genetic variation. Particular scrutiny has focused on a polymorphic N-terminal glutamine (Q) tract (CAG repeat) that shows population heterogeneity. Abnormal expansion of this tract underlies late-onset neurodegeneration, and in vitro the length correlates inversely with transcriptional activity. Yet the question of whether length variation within the range of normal human alleles affects cancer has produced discordant epidemiological results, in part due to interacting genetic and environmental factors in human disease. To test Q tract length effects, the mouse AR gene was converted to the human sequence (h/mAr), creating alleles with 12, 21, or 48 CAG repeats. These mice were grossly normal, but molecular analysis revealed allele-dependent differences in target gene expression. Further, when crossed with mice transgenic for a prostate-directed oncogene (TRAMP), Q tract length-dependent differences in cancer initiation and progression were evident. TRAMP mice with short Q tract ARs exhibited earlier but more slowly progressing disease than mice with median or long Q tract ARs. Q tract length also affected disease progression after castration, but in directions opposite to those in intact mice – the AR12Q allele delayed tumor detection whereas mice with the AR48Q allele fared worse. These experiments provided evidence for a causal relationship between a human polymorphism and a cancer phenotype. In man, Q tract length effects may only be significant at extremes of variation within the normal range and may vary with stage of disease. The h/mAR mice provide an experimental paradigm in which to dissect mechanisms by which Q tract length affects development and progression of prostate cancer. Some of these mechanisms may lead to better predictors of response to therapy and new treatments targeted to the human AR.

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Acknowledgments

This chapter summarizes work by members of the laboratory over many years, but particularly Megan A. Albertelli, D.V.M., Ph.D., Arno Scheller, Ph.D., Orla A. O'Mahony, Ph.D., and Michele Brogley, M.S. Numerous colleagues providing essential discussions included, from the University of Michigan, Drs. Andrew Lieberman, Mara Steinkamp, and Christopher Krebs; and, from the Fred Hutchinson Cancer Research Center, Norman Greenberg. The Robins laboratory has been supported by the NIH (NIDDK-RO1-56356, NCI-P50-CA69568, NIH-T32-RR07008) and the DOD (DOD17-02-1-0099, W81XWH-05-1-0105), as well as Core support from the University of Michigan Cancer Center (5 P30 CA46592) and the Michigan Diabetes Research and Training Center (5 P60 DK20572).

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  1. Department of Human Genetics, University of Michigan Medical School, Ann Arbor, 48109-0618, MI, USA

    Diane M. Robins

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Correspondence to Diane M. Robins .

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James Mohler Donald Tindall

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© 2009 Springer Science+Business Media, LLC

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Robins, D.M. (2009). The Role of the Androgen Receptor Polyglutamine Tract in Prostate Cancer: In Mice and Men. In: Mohler, J., Tindall, D. (eds) Androgen Action in Prostate Cancer. Springer, New York, NY. https://doi.org/10.1007/978-0-387-69179-4_12

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