Pellerino, AlessiaPriego, NeiblaBertero, LucaRicci, Alessia AndreaMangherini, LucaBruno, FrancescoBeano, AlessandraMittica, GloriaMistrangelo, MarinellaGarbossa, DiegoBosch-Barrera, JoaquimCassoni, PaolaValiente, ManuelSoffietti, RiccardoRudà, Roberta2026-02-262026-02-262025-12-01Neuro Oncol . 2025 Dec 1;27(12):3132-3144.https://hdl.handle.net/20.500.12105/27276This work was supported by ERC CoG [864759 to M.V.], ERANET-TRANSCAN-3 (TRANSCAN2021-2023) [M.V.] with funds from Instituto de Salud Carlos III/NextGenerationEU/PRTR (AC20/00114) and FC AECC (TRNSC213878VALI), AECC Coordinados [PRYCO234528VALI, M.V.], AECC postdoctoral fellowship (POSTD19016PRIE) [N.P.], ERANET-TRANSCAN-3 (TRANSCAN 2021-2023) with funds from the Italian Ministry of University and Research (D63C23000040001) [L.B.].A high pSTAT3 expression in reactive astrocytes surrounding brain metastases (BrM) promotes tumor growth in preclinical models. The impact of STAT3 expression on outcome of patients with BrM from breast cancer is unknown.The expression of pSTAT3 in reactive astrocytes of 100 resected BrM from breast cancer was investigated by immunohistochemistry and correlated with molecular subtypes, risk of intracranial recurrence and progression-free survival. To explore whether clinical findings could be replicated in preclinical models, we used two human BrM cell lines (triple-negative MDA231 and HER2-positive HCC1954-), and evaluated pSTAT3 expression on established BrM.High pSTAT3 expression in reactive astrocytes was detected in 57% of BrM, and prevailed in triple-negative (80.9%) over HER2-positive (43.2%) and luminal (33.3%) metastases (P = .002). A different pSTAT3 expression was confirmed in animal models: as it was detected in 50% of reactive astrocytes in triple-negative MDA231 BrM lesions compared with 13% in HER2-positive HCC1954-BrM lesions (P = .0001). Patients with high pSTAT3 expression in BrM displayed higher intracranial recurrence rate (66.7 vs 33.3%) (P = .0353), and shorter intracranial PFS (9 months vs 28 months) (P = .0002), and this finding was significant for triple-negative patients only (P = .0008).This study indicates that STAT3 expression prevails in reactive astrocytes surrounding triple-negative BrM in comparison to HER2-positive and luminal BrM, and these findings mirror those observed in animal models. A high STAT3 expression correlates with higher risk of intracranial recurrence and shorter progression-free survival, particularly in patients with triple-negative BrM.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/STAT3 expressionbrain metastasesbreast cancerreactive astrocytessilibininAttribution-NonCommercial-NoDerivatives 4.0 International4079595127123132-3144Neuro Oncolopen access