Upstream-binding protein-1 promotes breast tumorigenesis by inducing NRG2-mediated metastasis, plasticity, and macrophage polarization.

Upstream binding protein 1 (UBP1) is a transcription factor (TF) of the CP2/grainyhead family involved in various biological processes, including cancer cell proliferation, differentiation, and embryonic development. While other mammalian grainyhead-like TFs have been linked to different cancers, including breast cancer (BC), the role of UBP1 in BC remains unexplored. In this study, we provide a preliminary investigation into the novel functions of UBP1 in BC. Using online database screening, we first demonstrated that elevated UBP1 levels in breast carcinoma are associated with poor prognosis and adverse clinical outcomes. We further showed that UBP1 promotes epithelial-mesenchymal transition (EMT) and stemness in BC cells while regulating key signaling pathways, including the suppression of the PI3K-Akt pathway. Additionally, UBP1 modulates tumor metastasis by influencing tumor-associated macrophage (TAM) polarization, promoting an immunosuppressive macrophage phenotype, and driving tumor progression. Our findings highlight UBP1's pivotal role in BC progression through multiple mechanisms, including EMT induction, stemness maintenance, and macrophage polarization via activation of the NRG2/Akt axis. Moreover, higher UBP1 expression correlates with lower overall and recurrence-free survival, underscoring its potential as a prognostic marker and therapeutic target for aggressive BC.