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<p>The estrogen receptor (ER) drives growth in most breast cancers. Endocrine therapy reduces recurrence, however around 30% of cancers relapse. Many recurrences occur years later, with slowly proliferating, hard-to-treat disease. To study this, we generate slow-growing resistant cells that form small primary tumours but readily metastasise. Single-cell RNA sequencing (scRNAseq) reveals that endocrine therapy reprograms these cells, notably upregulating the Rac1 signalling component P-Rex1. We find in clinical cohorts that P-Rex1 is high in ER+ breast cancer, including in late recurrent disease. Intravital imaging demonstrates that Rac1 signalling is active in ER+ cells following endocrine therapy. Targeting the Rac1 pathway with small molecule inhibitors (NSC23766, R-ketorolac) reduces survival and motility in resistant cells, inhibits in vivo Rac1 activity, and reduces tumour burden when combined with tamoxifen in a drug-refractory patient derived xenograft model. This work identifies the P-Rex1/Rac1 axis as a potential therapeutic target for late recurring ER+ breast cancer.</p>

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Endocrine therapy reprogramming of breast cancer facilitates metastatic escape via upregulation of P-Rex1/Rac1 signalling

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月11日

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  • Kristine J. Fernandez,
  • Ghazal Sultani,
  • Max Nobis,
  • Brian Gloss,
  • Leila Eshraghi,
  • Amy E. McCart Reed,
  • Sarah Alexandrou,
  • Christine Lee,
  • Daniel L. Roden,
  • Emily I. Jones,
  • Maryam Hasha Simad,
  • Ewan K. A. Millar,
  • Nenad Bartonicek,
  • Samantha R. Oakes,
  • Fatima Valdes-Mora,
  • Yolanda Colino-Sanguino,
  • Ellie T. Y. Mok,
  • Hannah L. Williams,
  • Jamie R. Kutasovic,
  • Margaret C. Cummings,
  • Janett Stoehr,
  • Victoria Lee,
  • Kate Harvey,
  • Sunny Wu,
  • Sunil R. Lakhani,
  • Peter T. Simpson,
  • Thomas R. Cox,
  • Lisa M. Ooms,
  • Christina A. Mitchell,
  • Rob Salomon,
  • Alexander Swarbrick,
  • David Gallego-Ortega,
  • Elgene Lim,
  • Paul Timpson,
  • C. Elizabeth Caldon

摘要

The estrogen receptor (ER) drives growth in most breast cancers. Endocrine therapy reduces recurrence, however around 30% of cancers relapse. Many recurrences occur years later, with slowly proliferating, hard-to-treat disease. To study this, we generate slow-growing resistant cells that form small primary tumours but readily metastasise. Single-cell RNA sequencing (scRNAseq) reveals that endocrine therapy reprograms these cells, notably upregulating the Rac1 signalling component P-Rex1. We find in clinical cohorts that P-Rex1 is high in ER+ breast cancer, including in late recurrent disease. Intravital imaging demonstrates that Rac1 signalling is active in ER+ cells following endocrine therapy. Targeting the Rac1 pathway with small molecule inhibitors (NSC23766, R-ketorolac) reduces survival and motility in resistant cells, inhibits in vivo Rac1 activity, and reduces tumour burden when combined with tamoxifen in a drug-refractory patient derived xenograft model. This work identifies the P-Rex1/Rac1 axis as a potential therapeutic target for late recurring ER+ breast cancer.