The kallikrein 14 gene is down-regulated by androgen receptor signalling and harbours genetic variation that is associated with prostate tumour aggressiveness
Felicity Lose, Mitchell G. Lawrence, Srilakshmi Srinivasan
, Tracy O’Mara, Louise Marquart
, Suzanne Chambers, Robert A. Gardiner
, Joanne F. Aitken, Amanda B. Spurdle
, Jyotsna Batra, Judith A. Clements
, and the Australian Prostate Cancer BioResource
1 Molecular Cancer Epidemiology Group, Genetics and Population Health Division, Queensland Institute of Medical Research, 300 Herston Road, Herston, Brisbane, QLD 4006, Australia
2 Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Brisbane, QLD 4059, Australia
3 Statistics Unit, Queensland Institute of Medical Research, 300 Herston Road, Herston, Brisbane, QLD 4006, Australia
4 Griffith Health Institute, Griffith University, Southport, Brisbane, QLD 4222, Australia
5 Viertel Centre for Cancer Research, Cancer Council Queensland, Fortitude Valley, Brisbane, QLD 4004, Australia
6 University of Queensland Centre for Clinical Research, Royal Brisbane Hospital, Herston, Brisbane, QLD 4029, Australia
7 These authors contributed equally to this study.
8 Present address: Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia.
Kallikrein 14 (KLK14) has been proposed as a useful prognostic marker in prostate cancer, with expression reported to be associated with tumour characteristics such as higher stage and Gleason score. KLK14 tumour expression has also shown the potential to predict prostate cancer patients at risk of disease recurrence after radical prostatectomy. The KLKs are a remarkably hormone-responsive family of genes, although detailed studies of androgen regulation of KLK14 in prostate cancer have not been undertaken to date. Using in vitro studies, we have demonstrated that unlike many other prostatic KLK genes that are strictly androgen responsive, KLK14 is more broadly expressed and inversely androgen regulated in prostate cancer cells. Given these results and evidence that KLK14 may play a role in prostate cancer prognosis, we also investigated whether common genetic variants in the KLK14 locus are associated with risk and/or aggressiveness of prostate cancer in approximately 1200 prostate cancer cases and 1300 male controls. Of 41 single nucleotide polymorphisms assessed, three were associated with higher Gleason score (≥7): rs17728459 and rs4802765, both located upstream of KLK14, and rs35287116, which encodes a p.Gln33Arg substitution in the KLK14 signal peptide region. Our findings provide further support for KLK14 as a marker of prognosis in prostate cancer.
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