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Mutations at the Boundary of the Hinge and Ligand Binding Domain of the Androgen Receptor Confer Increased Transactivation Function

Flinders Cancer Centre (G.B., M.Y., N.M., J.B., D.J.H., V.R.M., W.D.T.) Flinders University and Flinders Medical Centre Adelaide SA 5042, Australia Institute for Molecular Biosciences (J.M.H.) University of Queensland Brisbane Qld 4072, Australia Department of Cell Biology and Department of Medicine (H.S.N., G.H., N.M.G.) aylor College of Medicine Houston, Texas 77030 Department of Cell Biology (R.J.M.) Urological Surgery and the Vanderbilt Cancer Center Nashville, Tennessee 37232

The androgen receptor (AR), a member of the steroid receptor superfamily of nuclear transcription factors, mediates androgen signaling in diverse target tissues. Here we report AR gene mutations identified in human prostate cancer and the autochthonous transgenic adenocarcinoma of the mouse prostate model that colocate to residues ⁶⁶⁸QPIF⁶⁷¹ at the boundary of the hinge and ligand-binding domain, resulting in receptors that exhibit 2- to 4-fold increased activity compared with wild-type AR in response to dihydrotestosterone, estradiol, progesterone, adrenal androgens, and the AR antagonist, hydroxyflutamide, without an apparent effect on receptor levels, ligand binding kinetics, or DNA binding. The expression of these or similar variants could explain the emergence of hormone refractory disease in a subset of patients. Homology modeling indicates that amino acid residues ⁶⁶⁸QPIF⁶⁷¹ form a ridge bordering a potential protein-protein interaction surface. The naturally occurring AR gene mutations reported in this study result in decreased hydrophobicity of this surface, suggesting that altered receptor-protein interaction mediates the precocious activity of the AR variants.

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