PROJECT SUMMARY Forty percent of patients with the most prevalent luminal hormone receptor positive (HR+) breast cancer (BCa) subtype are unresponsive to conventional endocrine therapy (ET) and readily present with incurable metastatic disease. Patients with ET resistant (ET-R) BCa exhibit an “endocrine-switch” to androgen receptor (AR)- dependent tumor growth and metastasis. Anti-androgens are emerging as promising therapy for other advanced BCa subtypes but surprisingly, AR overexpressing ET-R BCa cells are unresponsive to AR antagonists. Our new findings show constitutively active AR accumulate and evade the inhibitory actions of anti-androgen Enzalutamide (Enz). Hence, the objective of the current project is to design a therapeutic strategy to effectively target AR and prevent metastatic progression of ET-R BCa. We demonstrate that unlike other cancer models, persistent SUMO post-translational modification (PTM) of AR (SUMO-AR) occurs natively in acquired and intrinsic ET-R BCa cells. SUMO-PTM is a critical dynamic cellular process and an imbalance in SUMO-specific enzymes drive select types of BCa including basal and Myc- dependent BCa as reported by us and others. Independent of the established SUMO enzymatic system, we identify a dual SUMO-ubiquitin ligase that is druggable and destabilizes SUMO-AR in ET-R BCa. This proposal will delineate the regulatory control of this novel ligase in ET-R BCa and its role in Enz-response. Our new data suggests that constitutive SUMO-AR genomic activity requires interaction with a lncRNA. Hence, we will delineate how SUMO-AR/lncRNA interaction facilitates ligand-independent genomic activity in ET-R BCa cells. Finally, the proposed studies will test unique approaches to either 1) inhibit AR activity or 2) potentiate AR degradation versus the current standard Enz. In the process, we will generate novel therapeutics and evaluate clinically relevant compounds specifically for advanced ET-R BCa. Consistently, completion of the project will validate the need and establish the tools for more comprehensive translational studies on SUMO-AR in ET-R HR+ BCa.