title: 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.
authors.affiliation: Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China.
authors.forename: Xuxia
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China.
authors.forename: Defang
authors.initials: D
authors.lastname: Ding
authors.affiliation: Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China.
authors.forename: Junxiang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China.
authors.forename: Honghong
authors.initials: H
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009534:Niclosamide / Q000494:pharmacology*; D011839:Radiation, Ionizing; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D060509:Wnt3A Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D060509:Wnt3A Protein; D051176:beta Catenin; D009534:Niclosamide
keywords: Wnt/β-catenin signaling; niclosamide; radiosensitization; triple-negative breast cancer