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Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
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ARL3 Enhances ERα Stability via USP10 Deubiquitination to Promote Endocrine Resistance and Drive Mitochondrial

Han Li1,2, Yang Liu1,2, Zehao Cai1,2

  • 1Department of Breast and Thyroid Surgery, Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|October 5, 2025
PubMed

Insights

ADP-ribosylation factor-like protein 3 (ARL3) stabilizes estrogen receptor alpha (ERα) in ERα-positive breast cancer. Targeting ARL3 with A-1331852 inhibits tumor growth and enhances endocrine therapy efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Estrogen receptor alpha (ERα)-positive breast cancer progression and endocrine resistance mechanisms are not fully understood.
  • Identifying novel regulators of ERα activity is crucial for developing effective therapies.

Purpose of the Study:

  • To investigate the role of ADP-ribosylation factor-like protein 3 (ARL3) in ERα-positive breast carcinogenesis and endocrine resistance.
  • To elucidate the molecular mechanisms by which ARL3 influences ERα stability and function.

Main Methods:

  • Overexpression analysis of ARL3 in breast cancer cell lines and tissues.
  • Chaperone activity assays and direct binding studies between ARL3 and ERα.
  • Ubiquitination and degradation assays for ERα upon ARL3 modulation.
  • Analysis of downstream signaling pathways (mTOR/AMPK) and mitochondrial function.
  • Preclinical studies using ARL3 inhibitor A-1331852 in mouse models.

Main Results:

  • ARL3 is overexpressed in ERα-positive breast cancer and acts as a novel chaperone stabilizing ERα via direct binding.
  • ARL3 enhances ESR1-driven transcription and cell proliferation.
  • Genetic ablation of ARL3 leads to ERα ubiquitination-dependent degradation, activating mTOR/AMPK pathways and causing mitochondrial dysfunction.
  • ARL3 upregulates USP10, deubiquitinating ERα at K252.
  • ARL3 inhibitor A-1331852 suppresses tumor growth and synergizes with endocrine therapies.

Conclusions:

  • ARL3 is a critical regulator of ERα homeostasis through USP10, impacting ERα-positive breast cancer development and endocrine resistance.
  • ARL3 represents a promising therapeutic target and a potential biomarker for ERα-positive breast cancer.
Keywords:
ARL3ESR1Endocrine therapyHR+ breast cancerUSP10

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