Brain FGF2 and NCAM1 contribute to FGFR1-dependent progression of ER+ breast cancer brain metastases in young and aged hosts

Fox, M. S.; Jaramillo-Gomez, J. A.; Marquez-Ortiz, R. A.; Alvarez-Eraso, K. L. F.; Contreras Zarate, M. J.; Koliavas, S.; Kabos, P.; Serkova, N. J.; Sartorius, C. A.; Wellberg, E. A.; Cittelly, D. M.

doi:10.1101/2025.06.07.658373

bioRxiv · 10.1101/2025.06.07.658373

Brain FGF2 and NCAM1 contribute to FGFR1-dependent progression of ER+ breast cancer brain metastases in young and aged hosts

Fox, M. S.·Jaramillo-Gomez, J. A.·Marquez-Ortiz, R. A.·Alvarez-Eraso, K. L. F.·Contreras Zarate, M. J.·Koliavas, S.·Kabos, P.·Serkova, N. J.·Sartorius, C. A.·Wellberg, E. A.·Cittelly, D. M.

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Abstract

Estrogen receptor positive (ER+) breast cancer represents a significant proportion of breast cancer brain metastasis but remains understudied. Here, we report that FGFR1-amplification, a well-established driver of ER+ breast cancer endocrine resistance, promotes ER+ 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 promoted breast cancer brain metastasis in estrogen-treated young mice, but FGF2 levels and signaling decreased in the brain with aging and estrogen-depletion. Neuronal and astrocytic NCAM1, which remain unchanged in young and aged brains, promoted adhesion to neurons, migration, and growth of ER+ cells, suggesting that interactions with astrocytes and neurons facilitate early ER+ breast cancer brain metastasis colonization through FGFR1. Importantly, FDA-approved FGFR inhibitors effectively blocked 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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Fox, M. S., Jaramillo-Gomez, J. A., Marquez-Ortiz, R. A., Alvarez-Eraso, K. L. F., Contreras Zarate, M. J., Koliavas, S., Kabos, P., Serkova, N. J., Sartorius, C. A., Wellberg, E. A., Cittelly, D. M.. 2025-06-09. Brain FGF2 and NCAM1 contribute to FGFR1-dependent progression of ER+ breast cancer brain metastases in young and aged hosts. https://doi.org/10.1101/2025.06.07.658373

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