Abstract PS1-11-25: Fgfr1 promotes brain metastases of er+ breast cancer through canonical and non-canonical mechanisms in young and aged hosts

Abstract Estrogen receptor positive (ER+) breast cancer (BC) represents nearly 50% of all BC brain metastasis (BCBM) but remains understudied. Most ER+ BCBMs occur in postmenopausal women due to age or prior endocrine therapies, yet most in vivo ER+ BC models are estrogen (E2)-dependent and studied in young hosts. Thus, the mechanisms underlying metastatic progression in the aged/E2-depleted brain tumor microenvironment (TME) remain unknown. FGFR1-amplification (amp), a well-known driver of ER+ BC endocrine therapy resistance, was the only genomic alteration associated with increased risk of late recurrence in post-menopausal women with ER+ early BC on aromatase inhibitors, and FGFR aberrations are significantly higher in BCBM patients compared to non-BM in metastatic BC. While FGFRamp is often associated with auto-activation, TME-dependent activation of FGFR1 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+ PDX-derived cell lines showed higher BM incidence in FGFR1amp lines, and brain colonization was E2-dependent in young mice and E2-independent in aged hosts. FGFR1 knockdown (KD) did not alter 2D proliferation but decreased their growth in organotypic brain slices and their ability to colonize the brain in E2-high/young and E2-low/aged mice. Spatial transcriptomics of ER+ BCBMs and surrounding glial cells showed that while late-stage ER+ BCBMs are transcriptionally similar, aging and E2-depletion reduced FGF2 expression and FGF/FGFR signaling in surrounding glial cells, suggesting that TME-mediated paracrine activation of FGFR1 may be distinct in young and aged hosts. Since astrocytes were the main FGF2 source in the brain, we tested how changes in their FGF2 levels impact ER+ BC growth. Young astrocytes more effectively activated FGFR1 in ER+ BC cells than aged astrocytes and promoted FGFR1-dependent proliferation and mammosphere initiation of ER+ cells, suggesting that paracrine FGF2-driven FGFR1 activation contributes to ER+ BCBM growth in young hosts, but less in aged hosts. In the absence of FGF2, NCAM1, a cell adhesion molecule expressed in the surface of neurons and astrocytes, activates FGFR1 and contributes to neural development and synaptic plasticity. We found that like neurons, NCAM1 activated FGFR1 kinase activity and downstream signaling in ER+ BC, and induced differential expression of neuronal gene signatures including neural cell adhesion. FGFR1 KD decreased ER+ BC cell migration along neurites in co-culture with primary neurons and decreased the formation of synaptic puncta. NCAM1 KD in neuron-like SH-SY5Y neuroblastoma cells decreased migration of FGFR1amp ER+ BC cells, suggesting that FGFR1/NCAM1 facilitates interaction of ER+ BC cells with neurons and contributes to early BCBM colonization. Surprisingly, FGFR1 phosphorylation was higher in young versus aged mice at early stages of brain colonization but absent in all late-stage ER+ BCBMs, suggesting that paracrine activation of FGFR1 and interactions with neurons and astrocytes are critical for early BM colonization. Consistently, an FDA-approved FGFR inhibitor blocked ER+ BCBM when administered from early stages of BM colonization in young mice but did not block metastatic progression at late stages or in aged mice, suggesting limited efficacy of FGFR inhibitors to block non-kinase-dependent FGFR1 functions in vivo. Together, these studies suggest a novel mechanism whereby canonical and non-canonical activation of FGFR1 promote brain metastatic colonization of ER+ BC 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: M. S. Fox, J. A. Jaramillo-Gómez, R. Marquez Ortiz, K. Alvarez-Eraso, M. J. Contreras-Zárate, S. Koliavas, P. Kabos, N. J. Serkova, C. A. Sartorius, E. A. Wellberg, D. M. Cittelly. Fgfr1 promotes brain metastases of er+ breast cancer through canonical and non-canonical mechanisms in young and aged hosts abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-11-25.