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Updated: Apr 15, 2026

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Extracellular ATP promotes endocrine resistance in ER+ breast cancer through upregulation of PYGL

Yu-Qing Yu1, Xin-Yao Yu1, Xiao-Fei Li1

  • 1Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing, China.

Cell Death & Disease
|April 13, 2026
PubMed

Insights

Extracellular ATP promotes endocrine resistance in hormone receptor-positive breast cancer by upregulating glycogen phosphorylase L (PYGL). Targeting this pathway could improve endocrine therapy efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Hormone receptor (HR)-positive breast cancer is common, with endocrine therapy as the primary treatment.
  • Therapeutic resistance significantly limits the effectiveness of endocrine therapy.
  • The role of extracellular adenosine 5'-triphosphate (ATP) in endocrine resistance is not well understood.

Purpose of the Study:

  • To investigate the role of extracellular ATP in endocrine resistance in ER-positive breast cancer.
  • To elucidate the molecular mechanisms by which extracellular ATP mediates endocrine resistance.
  • To assess the clinical relevance of the identified pathway in breast cancer patients.

Main Methods:

  • Treatment of ER-positive breast cancer cells with endocrine agents and extracellular ATP.
  • Analysis of glycogen phosphorylase L (PYGL) expression and activity.
  • Investigation of the P2Y12-AhR signaling axis.
  • Assessment of glycolytic activity.
  • Correlation of PYGL expression with endocrine therapy sensitivity in organoids and clinical specimens.

Main Results:

  • Extracellular ATP upregulates PYGL expression in ER-positive breast cancer cells post-endocrine treatment.
  • Extracellular ATP activates the P2Y12-AhR signaling axis, leading to increased PYGL expression and enhanced glycolytic activity.
  • Elevated PYGL expression is associated with reduced endocrine therapy sensitivity in breast cancer models and patient tumors.

Conclusions:

  • Extracellular ATP-driven PYGL activation is a critical mechanism of endocrine resistance in breast cancer.
  • Targeting the extracellular ATP-P2Y12-AhR-PYGL pathway may enhance endocrine therapy efficacy.
  • This study identifies a novel therapeutic strategy for overcoming endocrine resistance in breast cancer.

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