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<p>Multiple next-generation molecules targeting estrogen receptor α (ERα) are being investigated in breast cancer clinical trials, encompassing thousands of women globally. Development of these molecules was partly motivated by the discovery of resistance-associated mutations in <i>ESR1</i> (encodes ERα). Here, we studied the impact of ERα antagonist/degraders against <i>Esr1</i> mutations expressed in mouse mammary glands. Inhibition of mutant ERα induced mixed-lineage cells, characterized by aberrant co-engagement of normally disparate master transcription factors. Lineage infidelity was also observed in <i>Esr1</i>-wild-type mice upon long-term estrogen deprivation. In ER<sup>+</sup> breast cancer biopsy specimens, heavily pretreated tumors with no <i>ESR1</i> mutation detected (NMD) frequently exhibited mixed-lineage features. <i>ESR1</i>-mutant tumors generally retained luminal features and higher ERα activity and exhibited an anti-proliferative response to the ERα antagonist giredestrant. <i>ESR1</i>-mutant tumors acquired mixed-lineage features following treatment. Lineage heterogeneity in advanced ER<sup>+</sup> breast cancer may underpin the differential benefit of investigational ERα therapeutics observed in <i>ESR1</i>-mutant versus NMD contexts.</p>

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ERα dysfunction caused by ESR1 mutations and therapeutic pressure promotes lineage plasticity in ER+ breast cancer

  • 期刊论文

  • 发表日期：

    2025年1月13日

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  • Jackson Liang,
  • Xiaosai Yao,
  • Patrick Aouad,
  • Bu-Er Wang,
  • Lisa Crocker,
  • Subhra Chaudhuri,
  • Yuxin Liang,
  • Spyros Darmanis,
  • Jennifer Giltnane,
  • Heather M. Moore,
  • Junko Aimi,
  • Ching-Wei Chang,
  • Mary R. Gates,
  • Jennifer Eng-Wong,
  • Marc Hafner,
  • Ciara Metcalfe

摘要

Multiple next-generation molecules targeting estrogen receptor α (ERα) are being investigated in breast cancer clinical trials, encompassing thousands of women globally. Development of these molecules was partly motivated by the discovery of resistance-associated mutations in ESR1 (encodes ERα). Here, we studied the impact of ERα antagonist/degraders against Esr1 mutations expressed in mouse mammary glands. Inhibition of mutant ERα induced mixed-lineage cells, characterized by aberrant co-engagement of normally disparate master transcription factors. Lineage infidelity was also observed in Esr1-wild-type mice upon long-term estrogen deprivation. In ER+ breast cancer biopsy specimens, heavily pretreated tumors with no ESR1 mutation detected (NMD) frequently exhibited mixed-lineage features. ESR1-mutant tumors generally retained luminal features and higher ERα activity and exhibited an anti-proliferative response to the ERα antagonist giredestrant. ESR1-mutant tumors acquired mixed-lineage features following treatment. Lineage heterogeneity in advanced ER+ breast cancer may underpin the differential benefit of investigational ERα therapeutics observed in ESR1-mutant versus NMD contexts.