Structure‐Based Androgen Receptor Gene Mutation Database: A Tool to Link Molecular Location and Receptor Function

Abstract

Background: Mutant androgen receptors (ARs) that arise in prostate cancer cells may contribute directly to the development of advanced disease in some patients. Therefore, a structural understanding of the altered receptors will provide new information about the molecular triggers that lead to androgen-independent disease or metastatic spread. Methods: Recognizing that molecular localization is required to understand the effect of AR mutations on receptor function, a structural model of the ligand-binding domain of AR was used to locate a comprehensive set of mutations in this domain that occur in prostate cancer. Substitutions were grouped into those that are likely to affect (1) ligand binding, (2) dimerization, or (3) coactivator binding/transactivation. Results: The results were tabulated and were used to develop a novel structure-based database linking molecular location with clinical observations for each mutant receptor expressed in the prostate cancer cells. Categories in the database can be cross-referenced to retrieve, for each mutation, molecular details of the substitution, clinical stage of the disease, treatment history, and functional phenotype of the mutant receptor. Conclusions: This database will be a resource for the development of therapeutics targeted to the AR and for understanding the role of ARs in androgen independence.