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 Bartoniček, Samantha R. Oakes, Fátima Valdés‐Mora, Yolanda Colino‐Sanguino, Ellie T. Y. Mok, Hannah 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
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.