Abstract
Estrogen receptor-positive breast cancer represents a significant proportion of breast cancer brain metastasis but remains understudied. Here we show that FGFR1-amplification, a well-established driver of estrogen receptor-positive breast cancer endocrine resistance, promotes estrogen receptor-positive breast cancer brain metastatic colonization in young and aged female mice, through both canonical FGF2/FGFR1 signaling and non-canonical NCAM1/FGFR1 interactions. Astrocytic FGF2-mediated paracrine activation of FGFR1 promotes breast cancer brain metastasis in estrogen-treated young mice, but FGF2 levels and signaling decrease in the brain with aging and estrogen-depletion. Neuronal and astrocytic NCAM1, which remain unchanged in young and aged brains, promote adhesion to neurons, migration, and growth of estrogen receptor-positive cells, suggesting that interactions with astrocytes and neurons facilitate early estrogen receptor-positive breast cancer brain metastasis colonization through FGFR1. Importantly, FDA-approved FGFR inhibitors effectively block early colonization but not late-stage brain metastases, suggesting prevention of FGFR1+ brain metastases as a window of opportunity for FGFR1 inhibitors.
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Acknowledgements
We would like to thank the Biorepository Core Facility and personnel at the CU Brain Tumor Biorepository for providing de-identified human tissues, Animal Imaging Shared Resource and Jenna Steiner, Genomics Shared Resource and Schuyler Lee, Functional Genomics Shared Resource, Human Immune Monitoring Shared Resource and Kimberly Jordan, and the Cell Technologies Shared Resource for their support of these studies. We would also like to thank Lianne Kraemer, Julia Maués, and Christine Hodgdon for their input and support.
Funding
This study was supported by DoD-BCRP W81XWH-22-1-0042 (DMC), R37CA227984 (DMC), T32CA190216 (MSF), F31CA294726 (MSF), University of Colorado Cancer Center Pilot Funds (DMC, CAS), the University of Colorado Cancer Center Support Grant (P30CA046934), and NIH High-End and SIFAR S10 Shared Instrumentation Grants (S10OD023485 and S10OD027023). DMC is additionally supported by R01CA290813. PK is supported by R01CA258766. EAW is supported by R01CA241156. Imaging was performed in the Advanced Light Microscopy Core facility of the NeuroTechnology Center at the University of Colorado Anschutz Medical Campus, which is supported in part by Diabetes Research Center Grant P30DK116073.
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M.S.F., J.A.J., R.A.M., K.L.F.A., M.J.C., T.C.P., E.N.B., S.N.K., N.J.S., C.A.S., E.A.W.: no conflicts. D.M.C.: Research grant support from Nuvation. PK: Clinical research grant support from Genentech, Menarini, Eli Lilly, AstraZeneca.
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Fox, M.S., Jaramillo-Gómez, J.A., Marquez-Ortiz, R.A. et al. Brain FGF2 and NCAM1 contribute to FGFR1-dependent progression of estrogen receptor-positive breast cancer brain metastases. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73726-5
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DOI: https://doi.org/10.1038/s41467-026-73726-5
