Mutations at the boundary of the hinge and ligand binding domain of the androgen receptor confer increased transactivation function

The androgen receptor (AR), a member of the steroid receptor superfamily of nuclear transcription factors, mediates androgen signaling in diverse targ et tissues. Here we report AR gene mutations identified in human prostate c ancer and the autochthonous transgenic adenocarcinoma of the mouse prostate model that colocate to residues (668)QPIF(671) at the boundary of the hing e and ligand-binding domain, resulting in receptors that exhibit 2- to 4-fo ld increased activity compared with wildtype AR in response to dihydrotesto sterone, estradiol, progesterone, adrenal androgens, and the AR antagonist, hydroxyflutamide, without an apparent effect on receptor levels, ligand bi nding kinetics, or DNA binding. The expression of these or similar variants could explain the emergence of hormone refractory disease in a subset of p atients. Homology modeling indicates that amino acid residues (668)QPIF(671 ) form a ridge bordering a potential protein-protein interaction surface. T he naturally occurring AR gene mutations reported in this study result in d ecreased hydrophobicity of this surface, suggesting that altered receptor-p rotein interaction mediates the precocious activity of the AR variants.