Brain FGF2 and NCAM1 contribute to FGFR1-dependent progression of estrogen receptor-positive breast cancer brain metastases.

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.