Endocrine therapy reprogramming of breast cancer facilitates metastatic escape via upregulation of P-Rex1/Rac1 signalling PMID: 42115169

ADC Targets in Oncology

2026-04-10

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.

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.