title: Effect of niclosamide on basal-like breast cancers.
abstract: Basal-like breast cancers (BLBC) are poorly differentiated and display aggressive clinical behavior. These tumors become resistant to cytotoxic agents, and tumor relapse has been attributed to the presence of cancer stem cells (CSC). One of the pathways involved in CSC regulation is the Wnt/β-catenin signaling pathway. LRP6, a Wnt ligand receptor, is one of the critical elements of this pathway and could potentially be an excellent therapeutic target. Niclosamide has been shown to inhibit the Wnt/β-catenin signaling pathway by causing degradation of LRP6. TRA-8, a monoclonal antibody specific to TRAIL death receptor 5, is cytotoxic to BLBC cell lines and their CSC-enriched populations. The goal of this study was to examine whether niclosamide is cytotoxic to BLBCs, specifically the CSC population, and if in combination with TRA-8 could produce increased cytotoxicity. Aldehyde dehydrogenase (ALDH) is a known marker of CSCs. By testing BLBC cells for ALDH expression by flow cytometry, we were able to isolate a nonadherent population of cells that have high ALDH expression. Niclosamide showed cytotoxicity against these nonadherent ALDH-expressing cells in addition to adherent cells from four BLBC cell lines: 2LMP, SUM159, HCC1187, and HCC1143. Niclosamide treatment produced reduced levels of LRP6 and β-catenin, which is a downstream Wnt/β-catenin signaling protein. The combination of TRA-8 and niclosamide produced additive cytotoxicity and a reduction in Wnt/β-catenin activity. Niclosamide in combination with TRA-8 suppressed growth of 2LMP orthotopic tumor xenografts. These results suggest that niclosamide or congeners of this agent may be useful for the treatment of BLBC.
authors.affiliation: Authors' Affiliations: Departments of Pathology, Biology, Biostatistics, Medicine, and Radiation Oncology; Division of Gynecologic Oncology; Southern Research Institute; and Division of Hematology and Onocology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Angelina I
authors.initials: AI
authors.lastname: Londoño-Joshi
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Arend
authors.forename: Laura
authors.initials: L
authors.lastname: Aristizabal
authors.forename: Wenyan
authors.initials: W
authors.lastname: Lu
authors.forename: Rajeev S
authors.initials: RS
authors.lastname: Samant
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Metge
authors.forename: Bertha
authors.initials: B
authors.lastname: Hidalgo
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.forename: Michael
authors.initials: M
authors.lastname: Conner
authors.forename: Andres
authors.initials: A
authors.lastname: Forero-Torres
authors.forename: Albert F
authors.initials: AF
authors.lastname: Lobuglio
authors.forename: Yonghe
authors.initials: Y
authors.lastname: Li
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Buchsbaum
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008819:Mice, Nude; D018295:Neoplasms, Basal Cell / Q000188:drug therapy* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D009534:Niclosamide / Q000494:pharmacology* / Q000627:therapeutic use; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C572208:TRA-8 monoclonal antibody; D009534:Niclosamide