Soluble E-cadherin-CXCL1-CXCR2 axis as a therapeutic vulnerability in inflammatory breast cancer brain metastasis

BACKGROUND: The brain is a common site of relapse in inflammatory breast cancer (IBC), an E-cadherin-positive, aggressive form of breast cancer. Elevated serum levels of soluble E-cadherin (sEcad), an 80-kDa fragment, correlated with poorer outcomes and increased brain metastases in patients with metastatic IBC. We hypothesize that sEcad is a driver of brain metastasis in IBC. METHODS: Serum sEcad levels from 348 IBC patients were quantified by ELISA. To examine sEcad function, we used recombinant sEcad protein and generated stable IBC cell lines by cloning and overexpressing Flag-tagged sEcad. Control and sEcad-overexpressing MDA-IBC3 and SUM149 cells were injected into SCID/Beige mice to evaluate brain metastasis burden and survival, and a brain-permeable CXCR2 inhibitor was also tested for efficacy in these models. RESULTS: Higher serum sEcad levels correlated with poorer overall survival, earlier metastasis, and increased brain metastasis. In vitro, recombinant sEcad and stable sEcad overexpression in IBC cell lines promoted invasion, resistance to anoikis, and activation of pro-survival NF-κβ signaling. In vivo, mice injected with sEcad-overexpressing IBC cells had increased metastatic burden and reduced overall and brain metastasis-free survival. Further, sEcad induced reactive astrocytosis through the CXCL1/CXCL8-CXCR2 axis, and treatment with a brain-permeable CXCR2 antagonist reduced metastatic burden and prolonged survival in the brain metastasis models. CONCLUSION: sEcad drives brain metastasis by promoting invasion and anoikis resistance in cancer cells and inducing an inflammatory brain microenvironment via a targetable CXCL1/CXCL8-CXCR2 axis. These findings uncover a novel and critical role for sEcad and highlight CXCR2 as a therapeutic target in patients with metastatic IBC.