BSBM-09 ASTROCYTES MEDIATE PARACRINE ACTIVATION OF FGFR1 TO ER+ BREAST CANCER BRAIN METASTASES

ER⁺ breast cancer (BC) accounts for ~50% of all BC brain metastases (BCBM) and is severely understudied. By contrast to BM from triple-negative and Her2⁺ BC, ER⁺ BCBM occurs mostly in post-menopausal women due to aging or endocrine therapy. Thus, specific interactions with cells within the aged/estrogen-depleted brain tumor microenvironment (TME) may promote ER⁺ BCBM. Amplification of FGFR1 (a TK receptor that binds canonically to FGF2) is the only genetic alteration shown to predict late recurrence of ER⁺ BC following anti-estrogen-therapies. Astrocytes promote BM by secreting growth factors that in a paracrine manner activate TK receptors in cancer cells that drive colonization. Thus, we hypothesize that paracrine activation of FGFR1 by astrocytes contributes to estrogen-independent ER⁺ BCBM outgrowth, and changes in FGFR1 ligand-expression in the brain TME may influence the ability of ER⁺ BC to colonize the brain niche. Using in vitro co-culture systems, we demonstrate that conditioned media from astrocytes (CMAst) promotes estrogen-independent proliferation and tumor-initiating capability of ER⁺ FGFR1-amplified PDX-derived cell lines (UCD65). CMAst activated FGFR1 and downstream signaling in ER⁺ cells, but FGFR1 inhibitors had modest ability to block this signaling, suggesting astrocytes activate FGFR1 dependent and independent pathways. FGFR1 KD impaired the growth of ER⁺ cells when cultured with CMAst but abolished their growth when co-cultured directly on astrocytes, suggesting FGFR1 is critical for cancer cell-astrocyte direct interactions. Young astrocytes promoted cancer cells proliferation more effectively than aged astrocytes and FGF2 decreased in astrocytes from aged mice compared to young mice, suggesting that FGF2/FGFR1 interactions promote ER⁺ growth in the young but not the old brain TME. Moreover, ER⁺ BC cells were able to invade in brain slices from old but not young mice, suggesting that loss of canonical FGF2/FGFR1 signaling (and possibly activation of non-canonical FGFR1 functions) promote metastases in the older brain TME.