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Carcinogenesis Advance Access originally published online on December 6, 2006
Carcinogenesis 2007 28(5):1032-1039; doi:10.1093/carcin/bgl236
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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PSA/KLK3 AREI promoter polymorphism alters androgen receptor binding and is associated with prostate cancer susceptibility

John Lai1,3,{dagger}, Mary-Anne Kedda2,3,*,{dagger}, Kimberly Hinze2,3, Robert L.G. Smith1,2,3, John Yaxley4, Amanda B. Spurdle5, C.Phillip Morris1,3, Jonathan Harris1,3 and Judith A. Clements1,3

1 Cluster for Molecular Biotechnology, School of Life Sciences and Science Research Centre
2 Centre for Health Research, School of Public Health
3 Institute of Health and Biomedical Innovation, Queensland University of Technology, Victoria Park Road, Kelvin Grove, Brisbane, QLD 4059, Australia
4 Brisbane Private Hospital, Brisbane, QLD 4000, Australia
5 Molecular Cancer Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, QLD 4029, Australia

* To whom correspondence should be addressed. Tel: +61 0 7 3864 9674; Fax: +61 0 7 3864 3369; Email: m.kedda{at}qut.edu.au

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.

Abbreviations: AR, androgen receptor; ARE, androgen response element; BPH, benign prostatic hyperplasia; CI, confidence interval; DBD, DNA-binding domain; DHT, dihydrotestosterone; EMSA, electrophoretic mobility shift assay; OR, odds ratio; SNP, single-nucleotide polymorphism; PCR, polymerase chain reaction; PSA, prostate-specific antigen; TNM, tumor, node, metastasis

{dagger} These authors contribute equally to this work.

Received August 14, 2006; revised October 27, 2006; accepted November 24, 2006.


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