Abstract IA001: Structural plasticity within the androgen receptor shapes oncogenic transcriptional programs

Abstract The androgen receptor (AR) is a nuclear receptor that governs gene expression programs required for prostate development and male phenotype maintenance. Advanced prostate cancers are characterized by AR hyperactivation and transcriptome expansion, in part, through AR amplification and interaction with oncoprotein cofactors. Targeted therapies that inhibit androgen synthesis or directly antagonize AR activity remain the cornerstone of treatment for advanced prostate cancer, yet resistance invariably emerges. Despite its biological importance, how AR domains and cofactors cooperate to bind DNA at the molecular level has been unclear. Using reconstitution biochemistry and single particle cryo-electron microscopy, we isolated three conformations of AR bound to DNA, showing that AR dimers are dynamic, with the dimer interface utilized by ancestral steroid receptors repurposed to facilitate binding to a wider substrate repertoire. We directly identify allosteric surfaces important for male development, and demonstrate that these interactions are promoted by binding to canonical AR binding motifs. We further demonstrate that in the context of prostate cancer, AR oncoprotein cofactors – including the ETS protein ERG – can hijack these interactions to promote aberrant AR activity to drive disease. Citation Format: Elizabeth V. Wasmuth. Structural plasticity within the androgen receptor shapes oncogenic transcriptional programs [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr IA001.