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<p>Hormone receptor (HR)–positive breast cancer accounts for approximately 60% of all breast cancer cases, for which endocrine therapy represents the mainstay of treatment; however, the development of therapeutic resistance substantially limits its clinical efficacy. Extracellular adenosine 5′-triphosphate (ATP) has been implicated as a key mediator of metastasis and chemotherapy resistance in multiple malignancies, including breast cancer, yet its role in endocrine resistance remains poorly defined. Here, we demonstrate that extracellular ATP upregulates glycogen phosphorylase L (PYGL) expression in ER-positive breast cancer cells following endocrine treatment, thereby promoting endocrine resistance. Mechanistically, extracellular ATP activates the P2Y12–AhR signaling axis, leading to increased PYGL expression, enhanced glycolytic activity, and subsequent resistance to endocrine therapy. Moreover, elevated PYGL expression was strongly associated with reduced endocrine therapy sensitivity in breast cancer organoids and clinical tumor specimens. Collectively, these findings identify extracellular ATP–driven PYGL activation as a critical mechanism underlying endocrine resistance and suggest that targeting this pathway may represent a promising strategy to improve endocrine therapy efficacy in breast cancer patients.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月13日

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  • Yu-Qing Yu,
  • Xin-Yao Yu,
  • Xiao-Fei Li,
  • Yi-Fan Cheng,
  • Yan-Ting Zhou,
  • Fang Mei,
  • Liang Weng,
  • Xin-Xia Tian

摘要

Hormone receptor (HR)–positive breast cancer accounts for approximately 60% of all breast cancer cases, for which endocrine therapy represents the mainstay of treatment; however, the development of therapeutic resistance substantially limits its clinical efficacy. Extracellular adenosine 5′-triphosphate (ATP) has been implicated as a key mediator of metastasis and chemotherapy resistance in multiple malignancies, including breast cancer, yet its role in endocrine resistance remains poorly defined. Here, we demonstrate that extracellular ATP upregulates glycogen phosphorylase L (PYGL) expression in ER-positive breast cancer cells following endocrine treatment, thereby promoting endocrine resistance. Mechanistically, extracellular ATP activates the P2Y12–AhR signaling axis, leading to increased PYGL expression, enhanced glycolytic activity, and subsequent resistance to endocrine therapy. Moreover, elevated PYGL expression was strongly associated with reduced endocrine therapy sensitivity in breast cancer organoids and clinical tumor specimens. Collectively, these findings identify extracellular ATP–driven PYGL activation as a critical mechanism underlying endocrine resistance and suggest that targeting this pathway may represent a promising strategy to improve endocrine therapy efficacy in breast cancer patients.