Endocrine therapy reprogramming of breast cancer facilitates metastatic escape via upregulation of P-Rex1/Rac1 signalling
- 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
2026-05-11
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.