Carcinogenesis Advance Access first published online on December 6, 2006
This version published online on December 13, 2006
Carcinogenesis, doi:10.1093/carcin/bgl236
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PSA/KLK3 AREI promoter polymorphism alters androgen receptor binding and is associated with prostate cancer susceptibility
1 Cluster for Molecular Biotechnology, School of Life Sciences and Science Research Centre, Queensland University of Technology, Brisbane, Australia
2 Centre for Health Research, School of Public Health, Queensland University of Technology, Brisbane, Australia
3 Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
4 Brisbane Private Hospital, Brisbane, Australia
5 Molecular Cancer Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia
Correspondence and request for reprints should be addressed to Dr. Mary-Anne Kedda, Institute of Health and Biomedical Innovation, Queensland University of Technology, Victoria Park Road, Kelvin Grove, Brisbane, QLD 4059, Australia. 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 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 AR, 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 interval [CI] = 1.36-6.52) and men with an A/G genotype had a 2.4-fold increased risk (95% CI = 1.23-4.81). Under a dominant model, the A allele conferred a 2.6-fold increased risk for prostate cancer (95% CI = 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 suggests that the presence of the A allele in AREI may, in part, account for the altered PSA regulation seen in prostate cancer.
Key Words: Kallikrein-related peptidase 3 (KLK3) • Prostate Specific Antigen (PSA) • Androgen Receptor (AR) • Androgen Response Element (ARE) • Single Nucleotide Polymorphism (SNP) • Prostate Cancer
* These authors contributed equally to this publication.
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