The TGF-β-regulated
Chloride Intracellular Channel 4 (CLIC4) is an essential participant in the formation of
breast cancer stroma. Here, we used data available from the TCGA and METABRIC datasets to show that CLIC4 expression was higher in breast
cancers from younger women and those with early-stage metastatic disease. Elevated CLIC4 predicted poor outcome in
breast cancer patients and was linked to the TGF-β pathway. However, these associations did not reveal the underlying biological contribution of CLIC4 to
breast cancer progression. Constitutive ablation of host Clic4 in two murine metastatic
breast cancer models nearly eliminated lung
metastases without reducing primary
tumor weight, while
tumor cells ablated of Clic4 retained metastatic capability in wildtype hosts. Thus, CLIC4 was required for host metastatic competence. Pre- and post-metastatic proteomic analysis identified circulating pro-metastatic soluble factors that differed in
tumor-bearing CLIC4-deficient and wildtype hosts. Vascular abnormalities and
necrosis increased in primary
tumors from CLIC4-deficient hosts. Transcriptional profiles of both primary
tumors and pre-metastatic lungs of
tumor-bearing CLIC4-deficient hosts were consistent with a microenvironment where inflammatory pathways were elevated. Altogether, CLIC4 expression in human breast
cancers may serve as a prognostic
biomarker; therapeutic targeting of CLIC4 could reduce primary
tumor viability and host metastatic competence.