BSBM-01 TARGETING CXCL1 - CXCR2 AXIS BLOCKS BRAIN METASTASIS IN INFLAMMATORY BREAST CANCER

Abstract BACKGROUND Brain metastasis is a frequent site of relapse in patients with inflammatory breast cancer (IBC) - a rare, highly aggressive variant of breast cancer. We discovered that soluble E-cadherin (sEcad), an 80-kDa E-cadherin fragment, correlates with increased brain metastasis risk and mortality in metastatic IBC patients. We further demonstrated that sEcad drives brain metastasis in HER2+ and triple-negative IBC mouse models. We hypothesize that sEcad induces specific cytokine production, activating astrocytes and priming the brain microenvironment for metastatic growth. METHODS sEcad-high and control IBC cells were injected into SCID/Beige mice to assess brain metastasis burden and survival. Human cytokine array analyzed conditioned medium from sEcad high and control cells. Clinical datasets compared expression and percent brain relapse rates. A brain-permeable CXCR2 inhibitor was tested for efficacy in IBC brain metastases. Multiplex quantitative imaging visualized cells in the brain metastatic microenvironment. RESULTS Higher serum sEcad levels were independently correlated with reduced overall survival and increased brain metastasis. Cytokine array and ELISA showed increased levels of pro-inflammatory cytokines CXCL1, DKK1 and CXCL8 in conditioned medium from sEcad-overexpressing IBC cells compared with control cells. In patient samples, CXCL1, CXCL8 and CXCR2, the receptor for CXCL1 and CXCL8, were expressed higher in brain metastases and had increased brain metastasis relapse. sEcad promoted reactive astrocytosis in vitro and in vivo, while CXCR2 inhibition reduced this effect. Treating sEcad-high brain metastases with a brain- permeable CXCR2 inhibitor reduced metastasis, lowered burden and prolonged survival in two IBC mouse models. Multiplexed immunofluorescence showed fewer reactive astrocytes in brain metastasis lesions treated with the CXCR2 inhibitor. CONCLUSION sEcad drives brain metastasis by promoting an inflammatory brain microenvironment via a targetable CXCL1/CXCL8-CXCR2 axis. Targeting this axis presents a promising therapeutic strategy to block brain metastasis in aggressive breast cancers.