Implications of Androgen Receptor Hyperstimulation by the FKBP51 L119P Mutation: No Evidence for Early Emergence of L119P in Prostate Cancer

Abstract

Objective: The immunophilin cochaperones, FKBP51 and FKBP52, have a modulating effect on steroid hormone receptors including the androgen receptor (AR). The differential effects seen by these immunophilins can be attributed to amino acid differences in the proline-rich loop; the proline at position 119 conferring AR potentiation capacity on FKBP52 and the leucine at this position in FKBP51 diminishing potentiation. FKBP51 can nevertheless potentiate AR activity in prostate cancer cells leading to accelerated growth. In addition, FKBP51 is regulated by AR, providing a feed-forward mechanism for FKBP51-mediated AR potentiation. These observations suggest that development of the FKBP51-L119P mutation in rostate cancer could lead to increased potentiation of AR and a more aggressive cancer phenotype. We tested this theory by examining the prevalence of FKBP51-L119P in a cohort of primary prostate tumours of increasing grade. Methods: A segment of the FKBP51 gene containing the leucine 119 codon was amplified from tumour DNA by PCR then subjected to digestion with BsmAI, a restriction enzyme having a recognition sequence incorporating the leucine 119 ‘CTC’ codon and occurring once in the amplicon. A subset of the prostate tumours was also examined for T > C conversion within the CTC codon by deep sequencing using the ion torrent system. Results: We were unable to detect the L119P mutation in any of the prostate cancers examined by restrictionenzyme analysis irrespective of tumour grade. In addition we found no evidence from ion torrent sequencing of early clonal development of cells with the L119P mutation in a subset of the tumours. Conclusion: We found no evidence to suggest that the L119P mutation contributes to an increasingly aggressive prostate cancer phenotype. However, tumour outgrowth favouring this mutation might occur in response to the low androgen environment and we propose examination for the L119P mutation in castrate-resistant prostate cancer.