title: Neuropilin-1 is expressed by breast cancer stem-like cells and is linked to NF-κB activation and tumor sphere formation.
abstract: Cancer stem cells (CSCs) initiate tumors and have a high resistance to conventional cancer therapy. Tranilast is an orally active drug of low toxicity that exerts inhibitory effects on breast CSCs. This appears to depend on its aryl hydrocarbon receptor (AHR) agonistic activity, but this receptor has diverse functions and it is unclear how CSCs are inhibited. CSCs generate tumor spheres in low-adherence cultures, and we employed the mammosphere-forming assay as a functional test for breast CSCs. Because NF-κB has a key role in mammosphere formation and CSC-mediated tumor initiation, we examined that pathway. We also examined the role of neuropilin-1 (Nrp1), which is a growth factor coreceptor linked to the tumorigenicity of some CSCs. We found that tranilast concurrently suppressed mammosphere formation, Nrp1 expression and constitutive NF-κB activation. Flow cytometric analysis revealed that a subpopulation of breast cancer cells bearing breast CSC markers also expressed Nrp1. A blocking anti-Nrp1 antibody suppressed mammosphere formation. We examined whether there was a link between Nrp1 and NF-κB activation. The siRNA knockdown of Nrp1 severely suppressed NF-κB activation and mammosphere formation. The phosphorylation of Akt and ERK1/2 was also reduced, but to a lesser extent. We conclude that Nrp1 plays a key role in mammosphere formation and this activity is linked to NF-κB activation. Thus, Nrp1 might be a target for therapy against breast CSCs, and the anticancer drug tranilast suppresses its expression.
authors.affiliation: Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael's Hospital, ON, Canada M5B 1W8. glinkay@smh.ca
authors.forename: Yelena
authors.initials: Y
authors.lastname: Glinka
authors.forename: Nada
authors.initials: N
authors.lastname: Mohammed
authors.forename: Venkateswaran
authors.initials: V
authors.lastname: Subramaniam
authors.forename: Serge
authors.initials: S
authors.lastname: Jothy
authors.forename: Gérald J
authors.initials: GJ
authors.lastname: Prud'homme
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3; D016328:NF-kappa B / Q000819:agonists / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D039942:Neuropilin-1 / Q000096:biosynthesis* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering / Q000235:genetics; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D062367:ortho-Aminobenzoates / Q000494:pharmacology
chemical_list: D016328:NF-kappa B; D034741:RNA, Small Interfering; D062367:ortho-Aminobenzoates; D039942:Neuropilin-1; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3; C012293:tranilast