Journal Article

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

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

2026

Overview

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. Endocrine therapies are the main adjuvant therapy for estrogen receptor positive breast cancer, but 30% of patients recur. Here, the authors discover that endocrine therapy upregulates Rac1 signalling component P-Rex1, and inhibition of Rac1 reduces tumour growth in refractory breast cancer models.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/51 / 14/10 / 45 / 45/91 / 631/67/1347 / 631/80/86/2341 / Aminoquinolines - pharmacology / Animals / Antineoplastic Agents, Hormonal - pharmacology / Antineoplastic Agents, Hormonal - therapeutic use / Autopsies / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cancer therapies / Cell cycle / Cell division / Cell Line, Tumor / Cell Movement - drug effects / Collagen / Drug Resistance, Neoplasm - drug effects / Endocrine therapy / Estrogen receptors / Estrogens / Female / Flow cytometry / Gene Expression Regulation, Neoplastic - drug effects / Guanine Nucleotide Exchange Factors - genetics / Guanine Nucleotide Exchange Factors - metabolism / Humanities and Social Sciences / Humans / Metastases / Metastasis / Mice / multidisciplinary / Neoplasm Metastasis / Pyrimidines - pharmacology / rac1 GTP-Binding Protein - antagonists & inhibitors / rac1 GTP-Binding Protein - genetics / rac1 GTP-Binding Protein - metabolism / Rac1 protein / Receptors / Receptors, Estrogen - metabolism / Science / Science (multidisciplinary) / Signal transduction / Signal Transduction - drug effects / Tamoxifen - pharmacology / Tamoxifen - therapeutic use / Therapeutic targets / Therapy / Tumors / Up-Regulation - drug effects / Xenograft Model Antitumor Assays / Xenotransplantation