Host CLIC4 is essential for breast cancer metastatic competence

Chloride Intracellular Channel 4 (CLIC4) expression is elevated in the stroma of many cancers. We show that CLIC4 expression is higher in breast cancers from younger women and early stage metastatic disease, portends poor prognosis, and is linked to TGF-ß expression. Two murine breast cancer models with lung metastases revealed that ablation of host Clic4 nearly eliminated lung metastases without reducing primary tumor size while Clic4 null tumor cells retained metastatic capability. Thus, CLIC4 is required for host metastatic competence. Deficiencies in circulating pro-metastatic soluble factors were detected in CLIC4 deficient hosts bearing primary tumors. Necrosis and vascular abnormalities were more abundant in primary tumors from CLIC4 deficient hosts than from CLIC4 proficient control hosts. Transcriptional profiles of lungs and primary tumors prior to the onset of metastases indicated that loss of host CLIC4 enhances an inflammatory microenvironment. Thus, CLIC4 expression in human breast cancers may serve as a prognostic biomarker, and targeting host CLIC4 could reduce metastatic competence. Overall design: Transcriptional profiles of lungs and primary tumors prior to the onset of metastases. The 6DT1 mouse mammary tumor explant cell line was injected orthotopically into the fourth mammary fat pad of wildtype or CLIC4 knockout syngeneic FVB/N mice. Lung tissue was isolated from wildtype and CLIC4 knockout mice at baseline or 14 days after orthografting. Primary tumor tissue was isolated at 14 days after orthografting.