Endocrine therapy reprogramming of breast cancer facilitates metastatic escape via upregulation of P-Rex1/Rac1 signalling
Abstract
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.
Article Details
Authors (35)
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
Garvan Institute of Medical Research, Sydney
Paul Timpson
C. Elizabeth Caldon