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

  • Nat Commun. 2026 May 11;17(1):3042. doi: 10.1038/s41467-026-70683-x.
Kristine J Fernandez  #  1 ,  Ghazal Sultani  #  1  2 ,  Max Nobis  3 ,  Brian Gloss  4 ,  Leila Eshraghi  1  2 ,  Amy E McCart Reed  5 ,  Sarah Alexandrou  1  2 ,  Christine Lee  1 ,  Daniel L Roden  1  2 ,  Emily I Jones  6 ,  Maryam Hasha Simad  1  2 ,  Ewan K A Millar  7  8 ,  Nenad Bartonicek  1 ,  Samantha R Oakes  2  9  10 ,  Fatima Valdes-Mora  2  11 ,  Yolanda Colino-Sanguino  11 ,  Ellie T Y Mok  1  2 ,  Hannah L Williams  1  12 ,  Jamie R Kutasovic  5 ,  Margaret C Cummings  5  13 ,  Janett Stoehr  1 ,  Victoria Lee  1 ,  Kate Harvey  1 ,  Sunny Wu  1  2 ,  Sunil R Lakhani  5 ,  Peter T Simpson  5 ,  Thomas R Cox  1  2 ,  Lisa M Ooms  6 ,  Christina A Mitchell  6 ,  Rob Salomon  14 ,  Alexander Swarbrick  1  2 ,  David Gallego-Ortega  1  2  15 ,  Elgene Lim  1  2  16 ,  Paul Timpson  1  2 ,  C Elizabeth Caldon  17  18
Affiliations
  • 1. Garvan Institute of Medical Research, Sydney, NSW, Australia.
  • 2. School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.
  • 3. Division of Cell Matrix Biology and Regenerative Medicine, Manchester Cell-Matrix Centre, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UK.
  • 4. Westmead Research Hub, Westmead Institute for Medical Research, Westmead, NSW, Australia.
  • 5. The University of Queensland, Faculty of Health, Medicine and Behavioural Sciences, Centre for Clinical Research, Brisbane, QLD, Australia.
  • 6. Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia.
  • 7. St George and Sutherland Clinical Campuses, School of Clinical Medicine, UNSW Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.
  • 8. Department of Anatomical Pathology, NSW Health Pathology, Kogarah, NSW, Australia.
  • 9. ANZUP Cancer Trials Group, Health Translation Hub, Randwick, Sydney, NSW, Australia.
  • 10. The George Institute for Global Health, Health Translation Hub, Randwick, Sydney, NSW, Australia.
  • 11. Cancer Epigenetic Biology and Therapeutics, Therapeutic Discovery Theme, Children's Cancer Institute, Sydney, NSW, Australia.
  • 12. Institute for Tissue Medicine and Pathology, University of Bern, Bern, Switzerland.
  • 13. Pathology Queensland, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
  • 14. Institute for Biomedical Materials and Devices, University of Technology Sydney, Sydney, NSW, Australia.
  • 15. School of Biomedical Engineering, Faculty of Engineering and IT, University of Technology Sydney, Ultimo, NSW, Australia.
  • 16. St Vincent's Hospital, Darlinghurst, Sydney, NSW, Australia.
  • 17. Garvan Institute of Medical Research, Sydney, NSW, Australia. [email protected].
  • 18. School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia. [email protected].
  • # Contributed equally.
PMID: 42115169 DOI: 10.1038/s41467-026-70683-x
Abstract

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.

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