PSA/KLK3 AREI promoter polymorphism alters androgen receptor binding and is associated with prostate cancer susceptibility

Lai, John, Kedda, Mary-Anne, Hinze, Kimberly E., Smith, Robert L. G., Yaxley, John, Spurdle, Amanda B., Morris, Charles P., Harris, Jonathan, & Clements, Judith A. (2007) PSA/KLK3 AREI promoter polymorphism alters androgen receptor binding and is associated with prostate cancer susceptibility. Carcinogenesis, 28(5), pp. 1032-1039.

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The proximal promoter of the kallikrein-related peptidase 3 gene (KLK3/PSA) contains a single-nucleotide polymorphism (G-158A) located within the second canonical half-site for the prostate-specific antigen (PSA) androgen response element 1 (AREI). Previous studies suggest that this polymorphism may be associated with higher PSA levels and increase prostate cancer risk. We have investigated the potential functional significance of this polymorphism and its association with prostate cancer susceptibility by genotyping the G-158A polymorphism in 209 men diagnosed with prostate cancer and 223 healthy control men in an Australian Caucasian population. Functional analyses of PSA AREI demonstrated that the A allele increased binding of AREI to the androgen receptor, as well as increasing transcriptional response to androgens. Association studies of the G-158A polymorphism demonstrated that men with an A/A genotype had a 3-fold increased risk for developing prostate cancer [95% confidence intervals (CIs) = 1.36-6.52] and men with an A/G genotype had a 2.4-fold increased risk (95% CIs = 1.23-4.81). Under a dominant model, the A allele conferred a 2.6-fold increased risk for prostate cancer (95% CIs = 1.37-4.96, P = 0.004). Taken together with the finding that the G-158A polymorphism is associated with an increased risk of prostate cancer in Australian men, our functional data suggest that the presence of the A allele in AREI may, in part, account for the altered PSA regulation seen in prostate cancer.

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52 citations in Web of Science®
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ID Code: 8855
Item Type: Journal Article
Refereed: Yes
Keywords: PSA, KLK3, Prostate Cancer, Polymorphism
DOI: 10.1093/carcin/bgl236
ISSN: 0143-3334
Subjects: Australian and New Zealand Standard Research Classification > BIOLOGICAL SCIENCES (060000) > GENETICS (060400)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > PUBLIC HEALTH AND HEALTH SERVICES (111700) > Epidemiology (111706)
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Past > QUT Faculties & Divisions > Faculty of Science and Technology
Current > Institutes > Institute of Health and Biomedical Innovation
Current > Schools > School of Nursing
Copyright Owner: Copyright 2007 (The authors): Licensed to Oxford University Press
Copyright Statement: This is an electronic version of an article published in [Carcinogenesis 28(5):pp. 1032-1039.]
Deposited On: 02 Aug 2007 00:00
Last Modified: 16 Apr 2014 23:03

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