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

DOI
Publisher DOI
PubMed ID
42115169
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.
Date Issued
2026-05-11
Publication Type
Article
Subject(s)
Language(s)
en
Author(s)
Fernandez, Kristine J
Sultani, Ghazal
Nobis, Max
Gloss, Brian
Eshraghi, Leila
McCart Reed, Amy E
Alexandrou, Sarah
Lee, Christine
Roden, Daniel L
Jones, Emily I
Simad, Maryam Hasha
Millar, Ewan K A
Bartonicek, Nenad
Oakes, Samantha R
Valdes-Mora, Fatima
Colino-Sanguino, Yolanda
Mok, Ellie T Y
Kutasovic, Jamie R
Cummings, Margaret C
Stoehr, Janett
Lee, Victoria
Harvey, Kate
Wu, Sunny
Lakhani, Sunil R
Simpson, Peter T
Cox, Thomas R
Ooms, Lisa M
Mitchell, Christina A
Salomon, Rob
Swarbrick, Alexander
Gallego-Ortega, David
Lim, Elgene
Timpson, Paul
Caldon, C Elizabeth
Additional Credits
Journal
Nature Communications
Publisher
Nature Research
ISSN
2041-1723
Access(Rights)
open.access
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