Abstract PS1-08-30: Arl3 enhances ERα stability via usp10 deubiquitination to promote endocrine resistance and drive mitochondrial metabolic reprogramming in hr+ breast cancer

Abstract The molecular mechanisms of estrogen receptor a (ERα)-positive breast carcinogenesis and endocrine resistance remain unclear. This study identifies ADP-ribosylation factor-like protein 3 (ARL3) as a key oncogenic regulator overexpressed in ERα-positive breast cancer cells and tissues. Mechanistically, ARL3 stabilizes ERα as a novel chaperone via direct binding, enhancing ESR1-driven transcription and cell proliferation. Genetic ablation of ARL3 induces ERα ubiquitination-dependent degradation, activating mTOR/AMPK pathways and causing mitophagy/mitochondrial dysfunction. ARL3 maintains ERα stability by upregulating USP10, which removes K48/K63-linked polyubiquitin chains from ERα at the K252 site. In preclinical models, the small-molecule inhibitor A-1331852 (targeting ARL3) potently suppresses ERα-positive tumor growth and synergizes with endocrine therapies. These findings establish ARL3 as a critical regulator of ERα homeostasis via USP10, highlighting its dual role as a biomarker and ARL3-targeted therapeutic for ERα-positive breast cancer. Citation Format: H. li, Y. Liu, Z. Cai, S. Gao, K. He, M. Shen, S. Liu. Arl3 enhances ERα stability via usp10 deubiquitination to promote endocrine resistance and drive mitochondrial metabolic reprogramming in hr+ breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-08-30.