{"doi":"10.1101/2025.06.07.658373","title":"Brain FGF2 and NCAM1 contribute to FGFR1-dependent progression of ER+ breast cancer brain metastases in young and aged hosts","abstract":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":567792,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1092556,"name":"Jenny A. Jaramillo-Gómez","orcid":"0009-0005-6416-0948","position":1,"is_corresponding":false},{"id":671882,"name":"Ricaurte Alejandro Marquez-Ortíz","orcid":"0000-0002-7188-6158","position":2,"is_corresponding":false},{"id":671884,"name":"Karen L.F. Alvarez-Eraso","orcid":"0000-0002-8187-0950","position":3,"is_corresponding":false},{"id":671883,"name":"María J. Contreras‐Zárate","orcid":"0000-0002-0045-549X","position":4,"is_corresponding":false},{"id":1472016,"name":"Stella Koliavas","orcid":"0009-0006-4165-8345","position":5,"is_corresponding":false},{"id":234998,"name":"Peter Kabos","orcid":"0000-0003-1500-471X","position":6,"is_corresponding":false},{"id":132345,"name":"Natalie J. Serkova","orcid":"0000-0002-4573-3895","position":9,"is_corresponding":false},{"id":292451,"name":"Carol A. Sartorius","orcid":"0000-0002-9170-3988","position":10,"is_corresponding":false},{"id":381032,"name":"Elizabeth A. Wellberg","orcid":"0000-0001-7342-390X","position":11,"is_corresponding":false},{"id":267508,"name":"Diana M. Cittelly","orcid":"0000-0002-8392-0800","position":12,"is_corresponding":false},{"id":1472015,"name":"Morgan S. Fox","orcid":"0000-0001-6310-4155","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T02:56:48.183032Z","pmid":"40666846","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}