What question did this study set out to answer?

This research aims to understand the role of Arl3 in regulating ERα stability and its implications for endocrine resistance in breast cancer.

February 19, 2026

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

Key Points

This research aims to understand the role of Arl3 in regulating ERα stability and its implications for endocrine resistance in breast cancer.
Identified ARL3 as an oncogenic regulator in ERα-positive breast cancer cells.
Examined the mechanism by which ARL3 enhances ERα stability via USP10.
Utilized preclinical models to assess the effects of A-1331852 on ERα-positive tumor growth.
ARL3 stabilizes ERα by preventing its degradation through ubiquitination.
Inhibition of ARL3 leads to mitochondrial dysfunction and activates mTOR/AMPK pathways.
The small-molecule inhibitor A-1331852 effectively suppresses ERα-positive tumor growth.

Abstract

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.

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