Insights from AR Gene Mutations

  • Grant Buchanan
  • Eleanor F. Need
  • Tina Bianco-Miotto
  • Norman M. Greenberg
  • Howard I. Scher
  • Margaret M. Centenera
  • Lisa M. Butler
  • Diane M. Robins
  • Wayne D. TilleyEmail author


The accumulation of somatic mutations on the background of natural germline variation is one of the fundamental mechanisms underpinning both disease and the development and progression of perhaps all tumors. For example, germline inactivating mutations in one allele of a tumor suppressor gene (TSG) (e.g., p53 or BRCA1) predisposes an individual to a lifetime of increased risk of cancer in particular tissues. In those cases, tumors commonly arise after somatic inactivation of the second TSG allele, and are often characterized by a younger age of onset and a more aggressive phenotype than tumors arising in the same tissues without a common or dominant genetic predisposition. A small proportion of prostate cancers do indeed occur in a hereditary manner, but it has been difficult to attribute inheritance and risk to a single gene. Even for the monoallelic androgen receptor (AR) gene on the X chromosome, which exhibits variously traits of an at-risk allele, oncogene, and mediator of prostate cancer progression and therapy resistance, inactivating germline variation in the AR is essentially nonexistent in this disease. Instead, germline AR variants often underpin the relatively common inherited syndrome of androgen insensitivity (AIS). In contrast, however, somatic variation of the AR is potentially a frequent event during tumor progression.

As a consequence of these complexities, unraveling the precise role of the AR at each stage of prostate cancer progression, and indeed in different prostatic compartments or populations of tumor cells is challenging. In this chapter, we detail how the identification and characterization of somatic AR variants arising in prostate cancer has provided crucial information on (1) the role of the receptor throughout disease etiology and the emergence of castrate-recurrent disease, (2) the fine functional subdomain structure of the AR, (3) the oncogenic potential of aberrant AR signaling, and (4) new approaches to targeting AR function in disease management.


Prostate Cancer Androgen Receptor Androgen Receptor Signaling Androgen Receptor Activity Androgen Receptor Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors acknowledge the contributions of Drs. Rene Chmelar and Guangzhou Han (Fred Hutchinson Cancer Research Center, University of Washington) and technical assistance of Ms. Joanna Treloar. The authors are supported by the Prostate Cancer Foundation of Australia (GB, ID#Y102), the National Health and Medical Research Council of Australia (WDT, ID#453662), The United States Department of Defense (WDT, ID#PC060443), and a SPORE Grant from the National Cancer Institute (DMR, NCI P50 CA69568). GB holds a National Health and Medical Research Council of Australia CJ Martin Biomedical Fellowship. EFN is a recipient of a Freemasons Foundation Postdoctoral Fellowship.


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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Grant Buchanan
    • 1
  • Eleanor F. Need
    • 1
  • Tina Bianco-Miotto
    • 1
  • Norman M. Greenberg
    • 1
  • Howard I. Scher
    • 1
  • Margaret M. Centenera
    • 1
  • Lisa M. Butler
    • 1
  • Diane M. Robins
    • 1
  • Wayne D. Tilley
    • 1
    Email author
  1. 1.Dame Roma Mitchell Cancer Research LaboratorySchool of MedicineUniversity of Adelaide/Hanson InstituteSAAustralia

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