Abstract 2076: FGFR1 drives progression of ER+ breast cancer brain metastases in young and aged hosts.

Abstract The purpose of these studies is to define mechanisms that drive estrogen receptor positive (ER+) breast cancer brain metastasis (BCBM) colonization and outgrowth. Most ER+ BCBMs arise in postmenopausal women due to prior endocrine therapies or age, yet most in vivo ER+ breast cancer (BC) models require estrogen (E2) supplementation and use young hosts. Thus, the mechanisms underlying metastatic progression in the aged/E2-depleted brain tumor microenvironment (TME) remain unknown. FGFR1-amplification (amp), an established driver of ER+ BC endocrine therapy resistance, was the only genomic alteration associated with increased late recurrence in post-menopausal women with ER+ BC on aromatase inhibitors, and FGFR aberrations are enriched in BCBM patients compared to non-BM metastatic BC. While FGFR1amp often causes auto-activation, TME-dependent FGFR1 activation has emerged as an important mechanism modulating its activity. Here, we tested the hypothesis that canonical and non-canonical activation of FGFR1 by astrocytes and neurons promotes FGFR1-dependent ER+ BCBM in E2-high young and E2-low aged hosts. Intracardiac injection of ER+ cells showed that FGFR1amp lines had higher BM incidence, and were E2-dependent in young but not aged hosts. FGFR1 knockdown (KD) did not alter proliferation but decreased BCBM in both E2-high/young and E2-low/aged mice. Spatial transcriptomics of the ER+ BCBMs TME showed that aging and E2-depletion reduced FGF2 expression and FGF/FGFR signaling in surrounding glial cells, suggesting that TME-driven FGFR1 activation may be distinct in young and aged hosts. In the normal brain, NCAM1, an adhesion molecule expressed on neurons and astrocytes, can activate FGFR1. We found that NCAM1 activated FGFR1 kinase activity and downstream signaling in ER+ BC cells, and induced differential expression of neuronal gene signatures including neural cell adhesion. FGFR1 KD reduced ER+ BC cell migration along neurites in co-culture with primary neurons and decreased synaptic puncta. NCAM1 KD in neuron-like SH-SY5Y cells also decreased ER+ cell migration, suggesting that FGFR1/NCAM1 facilitates ER+ BC interactions with neurons, contributing to early brain colonization. Activated FGFR1 was higher in young versus aged mice at early stages of colonization but absent in late-stage ER+ BCBMs, suggesting that paracrine FGFR1 activation and interactions with neurons and astrocytes are critical for early colonization. Consistently, an FDA-approved FGFR inhibitor blocked ER+ BCBM when administered at early stages of colonization in young mice but had no effect at late stages or in aged mice. Together, these studies suggest a novel mechanism whereby canonical and non-canonical activation of FGFR1 promote ER+ BCBM colonization in young and aged/E2-depleted hosts, and caution that FGFR1 inhibition may only be effective to prevent but not to treat BMs. Citation Format: Morgan S. Fox, Jenny A. Jaramillo-Gómez, R. Alejandro Marquez-Ortiz, Karen L. Alvarez-Eraso, Maria J. Contreras-Zárate, Trinh C. Pham, Elaina N. Barela, Stella Koliavas, Peter Kabos, Carol A. Sartorius, Elizabeth A. Wellberg, Diana M. Cittelly. FGFR1 drives progression of ER+ breast cancer brain metastases in young and aged hosts [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 2076.