Characterisation of androgen receptor mutations identified from prostate cancer patients
Mutations of the AR are implicated as one of the key components in the development of prostate cancer and its poor prognosis to treatment. As prostate cancer is the second leading cause of cancer related death in Caucasian men much interest is currently focused on understanding it mechanisms of development. At present around fifty AR prostate cancer mutations have been reported in the androgen receptor mutation database, most of which have been either incompletely or poorly characterised. This study aims to clarify some of the molecular consequences of specific prostate cancer mutations that have been mapped to the receptor ligand-binding domain (LBD). It was observed that certain mutations such as the T877A and H874Y mutations were altered in ligand responsiveness to non-androgen ligands as has been previously reported, and that the Q798E mutation was also activated to some extent with progesterone. Other mutations such as D879G and V757A appeared to have a reduced transactivation response when stimulated by androgens in cell culture experiments. Gross experimental analysis of the mutant protein structures revealed that there were no major changes in the conformation of any of the proteins compared to wildtype. While modelling analysis of the ligand binding domain DHT bound crystal structure using the Swissprot Deepview programme revealed that several of the mutations resulted in more minor structural alterations such as altered H bonding or steric clashes. Finally several mutant proteins were revealed to have an altered interaction with p160 co-activator proteins in vitro. Most significant of these were the H874Y and the K720E AR mutants, which were also shown to be enhanced to a greater extent by the presence of certain co-activators in in vivo cell culture experiments.