The β-catenin signaling pathway induces aggressive potential in breast cancer by up-regulating the chemokine CCL5

beta-Catenin signaling plays a pivotal role in the genesis of a variety of malignant tumors, but its role in breast cancer has not been fully elucidated. Here, we examined whether deregulation of beta-catenin signaling is related to the aggressive characteristics of certain types of breast cancers. Analysis of cytokine levels in MDA-MB-231 cells overexpressing a constitutively active form of beta-catenin (CA beta-catenin) revealed a higher level of CCL5 expression. Cells transfected with CA beta-catenin or stimulated with recombinant CCL5 exhibited increased cell invasion activity and spheroid formation in vitro. Furthermore, CA beta-catenin-transfected MDA-MB-231 cells formed larger tumor masses that contained more Ki-67-positive cells and infiltrating lymphocytes than did the control cells. An inhibitor of CCR5 and a pan-CXCR neutralizing antibody dramatically reduced CA beta-catenin-promoted activities. In addition to CCL5, 6-BIO, a chemical activator of beta-catenin, induced cell invasion and spheroid formation in MDA-MB-231 cells. Furthermore, high levels of nuclear beta-catenin accumulation were detected in breast cancer in patients with metastasis but not in those without metastasis. Nuclear beta-catenin localization is related to increased CCL5 production in breast cancer. These findings suggest that beta-catenin expression enhances tumor progression via chemokine production in breast cancers and that beta-catenin signaling is a critical regulator of the aggressive traits of breast cancers. (C) 2015 Elsevier Inc. All rights reserved.