Endocrine therapy reprogramming of breast cancer facilitates metastatic escape via upregulation of P-Rex1/Rac1 signalling
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.
Authors
- Hannah Williams (ORCID: https://orcid.org/0000-0003-1828-9845)
- Janett Stoehr (ORCID: https://orcid.org/0000-0002-4198-3520)
- Max Nobis (ORCID: https://orcid.org/0000-0002-1861-1390)
- Ellie T. Y. Mok (ORCID: https://orcid.org/0009-0003-7750-3335)
- Amy E. McCart Reed
- Catherine Elizabeth Caldon (ORCID: https://orcid.org/0000-0003-1392-3472)
- Sarah Alexandrou (ORCID: https://orcid.org/0000-0003-1186-6507)
- Kate Harvey (ORCID: https://orcid.org/0000-0002-2155-5203)
- David Gallego‐Ortega (ORCID: https://orcid.org/0000-0002-2347-7835)
- Yolanda Colino‐Sanguino (ORCID: https://orcid.org/0000-0003-0128-5864)
- Alexander Swarbrick (ORCID: https://orcid.org/0000-0002-3051-5676)
- Fátima Valdés‐Mora (ORCID: https://orcid.org/0000-0001-7490-0114)
- Nenad Bartoniček (ORCID: https://orcid.org/0000-0003-2144-1887)
- Christina A. Mitchell (ORCID: https://orcid.org/0000-0001-9372-3192)
- Ghazal Sultani
- Paul Timpson (ORCID: https://orcid.org/0000-0002-5514-7080)
- Lisa M. Ooms (ORCID: https://orcid.org/0000-0002-8918-9932)
- Ewan K.A. Millar (ORCID: https://orcid.org/0000-0002-9778-3253)
- Emily I. Jones (ORCID: https://orcid.org/0000-0002-0605-884X)
- Leila Eshraghi
- Margaret C. Cummings (ORCID: https://orcid.org/0000-0002-7657-0240)
- Sunny Wu
- Christine Lee
- Victoria Lee
- Brian Gloss
- Maryam Hasha Simad
- Samantha R. Oakes
- Daniel L. Roden
- Rob Salomon (ORCID: https://orcid.org/0000-0003-4504-2901)
- Kristine J. Fernandez
- Sunil R. Lakhani (ORCID: https://orcid.org/0000-0003-1879-2555)
- Elgene Lim (ORCID: https://orcid.org/0000-0001-8065-8838)
- Jamie R. Kutasovic
- Thomas R. Cox (ORCID: https://orcid.org/0000-0001-9294-1745)
- Peter T. Simpson (ORCID: https://orcid.org/0000-0002-4816-8289)
Institutions
- University of Technology Sydney (AU)
- University of Bern (CH)
- New South Wales Department of Health (AU)
- Garvan Institute of Medical Research (AU)
- The University of Queensland (AU)
- Sutherland Hospital (AU)
- Royal Brisbane and Women's Hospital (AU)
- Discovery Institute (US)
- Wellcome Centre for Cell-Matrix Research (GB)
- Cancer Institute of New South Wales (AU)
- UNSW Sydney (AU)
- St Vincent's Hospital Sydney (AU)
- The George Institute for Global Health (AU)
- Children's Cancer Institute Australia (AU)
- St Vincent's Clinic (AU)
- Westmead Institute for Medical Research (AU)
- Australian and New Zealand Urogenital and Prostate Cancer Trials Group (AU)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-05-11
- DOI
- https://doi.org/10.1038/s41467-026-70683-x
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Breast Cancer Foundation
- National Health and Medical Research Council