Abstract INTRODUCTION: Brain metastases occur in approximately 20% of breast cancer patients. These secondary lesions exhibit distinct phenotypic and genomic alterations compared to primary breast tumours, often driven by specific transcription factors. Identifying such factors may reveal novel therapeutic targets for treating brain metastases. We investigate FOXM1 as a key regulator in breast cancer brain metastasis, highlighting it as a potential prognostic and therapeutic marker. MATERIALS AND METHODS: We performed RNA sequencing on 45 paired patient samples of primary breast tumours and corresponding brain metastases. Gene co-expression network analysis was conducted to identify preserved modules, focusing on the FOXM1-driven module. FOXM1 expression levels were assessed across patient cohorts to evaluate their correlation with survival outcomes and enrichment in tumours that progressed to brain metastasis. The impact of FOXM1 silencing on tumorigenicity and metastatic potential was investigated using breast-to-brain metastatic cell lines and in vivo models, with subsequent analysis of metastatic cluster formation and cellular proliferation. RESULTS: The FOXM1-driven gene module was conserved in brain metastases and associated with poor clinical outcomes, including reduced overall survival. High FOXM1 expression was notably enriched in tumours that relapsed in the brain and correlated with diminished recurrence-free survival. Genetic and pharmacological inhibition of FOXM1 significantly impacted proliferation across multiple models of breast cancer brain metastasis representing all major subtypes. Transcriptomic analysis following FOXM1 silencing revealed the regulation of key pathways, including mTOR, TGF-β, EGFR, and epithelial-mesenchymal transition (EMT). Genetic silencing of FOXM1 in vivo models significantly inhibited the formation and size of brain metastasis clusters, reducing both proliferation and metastatic capacity. CONCLUSION: FOXM1 is a critical regulator of breast cancer brain metastasis. Inhibition of FOXM1 hinders metastatic growth in the brain and improves survival-related outcomes. Targeting FOXM1 may signify a promising therapeutic strategy for patients with breast cancer brain metastasis. These findings underscore the importance of FOXM1 in brain metastases progression and suggest that targeting it could offer a novel therapeutic avenue. Citation Format: Shannon Cartay Kalsi, Lara Luzietti, Aoibheann Dowd, Aoibhín M. Powell, Gabriela Gomez, Jason McGrath, Nicola S. Cosgrove, Hian Hui Young, Arnold D. Hill, Stefan Prekovic, Leonie S. Young, Damir Varešlija. FOXM1 as a key regulator of metastatic outgrowth in brain metastasis of breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5968.
Kalsi et al. (Fri,) studied this question.