Niclosamide sensitizes triple-negative breast cancer cells to ionizing radiation in association with the inhibition of Wnt/β-catenin signaling

Abstract

Triple-negative breast cancer (TNBC) is one of the most difficult breast cancers to treat because there is no targeted treatment, and conventional cytotoxic chemotherapy followed by adjuvant radiation therapy is the standard of care for patients with TNBC. We herein reported that ionizing radiation (IR) induced Wnt3a, LRP6 and β-catenin expression and consequently activated Wnt/β-catenin signaling in TNBC MDA-MB-231, MDA-MB-468 and Hs578T cells. Moreover, depletion of β-catenin by shRNA sensitized TNBC cells to IR, whereas treatment of Wnt3a protein or overexpression of β-catenin resulted in radioresistance of TNBC cells. Niclosamide, a potent inhibitor of Wnt/β-catenin signaling, not only inhibited constitutive Wnt/β-catenin signaling, but also blocked IR-induced Wnt/β-catenin signaling in TNBC cells. In addition, niclosamide sensitized TNBC cells to IR, prevented Wnt3a-induced radioresistance, and overcame β-catenin-induced radioresistance in TNBC cells. Importantly, animals treated with the combination of niclosamide and γ-ray local tumor irradiation had significant inhibition of MDA-MB-231 tumor growth compared with treated with local tumor irradiation alone. These findings indicate that Wnt/β-catenin signaling pathway plays an important role in the development of radioresistance of TNBC cells, and that niclosamide had significant radiosensitizing effects by inhibiting Wnt/β-catenin signaling in TNBC cells. Our study also provides rationale for further preclinical and clinical evaluation of niclosamide in TNBC management.