title: Niclosamide inhibits epithelial-mesenchymal transition and tumor growth in lapatinib-resistant human epidermal growth factor receptor 2-positive breast cancer.
abstract: Acquired resistance to lapatinib, a human epidermal growth factor receptor 2 kinase inhibitor, remains a clinical problem for women with human epidermal growth factor receptor 2-positive advanced breast cancer, as metastasis is commonly observed in these patients. Niclosamide, an anti-helminthic agent, has recently been shown to exhibit cytotoxicity to tumor cells with stem-like characteristics. This study was designed to identify the mechanisms underlying lapatinib resistance and to determine whether niclosamide inhibits lapatinib resistance by reversing epithelial-mesenchymal transition. Here, two human epidermal growth factor receptor 2-positive breast cancer cell lines, SKBR3 and BT474, were exposed to increasing concentrations of lapatinib to establish lapatinib-resistant cultures. Lapatinib-resistant SKBR3 and BT474 cells exhibited up-regulation of the phenotypic epithelial-mesenchymal transition markers Snail, vimentin and α-smooth muscle actin, accompanied by activation of nuclear factor-кB and Src and a concomitant increase in stem cell marker expression (CD44(high)/CD24(low)), compared to naive lapatinib-sensitive SKBR3 and BT474 cells, respectively. Interestingly, niclosamide reversed epithelial-mesenchymal transition, induced apoptosis and inhibited cell growth by perturbing aberrant signaling pathway activation in lapatinib-resistant human epidermal growth factor receptor 2-positive cells. The ability of niclosamide to alleviate stem-like phenotype development and invasion was confirmed. Collectively, our results demonstrate that lapatinib resistance correlates with epithelial-mesenchymal transition and that niclosamide inhibits lapatinib-resistant cell viability and epithelial-mesenchymal transition. These findings suggest a role of niclosamide or derivatives optimized for more favorable bioavailability not only in reversing lapatinib resistance but also in reducing metastatic potential during the treatment of human epidermal growth factor receptor 2-positive breast cancer.
authors.affiliation: Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong Univerisity School of Medicine, Shanghai, China; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Junjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong Univerisity School of Medicine, Shanghai, China; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Chen
authors.affiliation: Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Toby
authors.initials: T
authors.lastname: Ward
authors.affiliation: Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong Univerisity School of Medicine, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Bockhorn
authors.affiliation: Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Liu
authors.affiliation: Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong Univerisity School of Medicine, Shanghai, China.
authors.forename: Gen
authors.initials: G
authors.lastname: Wang
authors.affiliation: Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: mpegram@stanford.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Pegram
authors.affiliation: Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong Univerisity School of Medicine, Shanghai, China. Electronic address: kwshen@medmail.com.cn.
authors.forename: Kunwei
authors.initials: K
authors.lastname: Shen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009534:Niclosamide / Q000494:pharmacology*; D010641:Phenotype; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D016328:NF-kappa B; D009534:Niclosamide; D016392:Proto-Oncogene Proteins pp60(c-src); D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; C508053:ERBB2 protein, human
keywords: Breast cancer; Epithelial-mesenchymal transition; Human epidermal growth factor receptor 2; Lapatinib resistance; Niclosamide