title: NF-kappaΒ-inducing kinase regulates stem cell phenotype in breast cancer.
abstract: Breast cancer stem cells (BCSCs) overexpress components of the Nuclear factor-kappa B (NF-κB) signaling cascade and consequently display high NF-κB activity levels. Breast cancer cell lines with high proportion of CSCs exhibit high NF-κB-inducing kinase (NIK) expression. The role of NIK in the phenotype of cancer stem cell regulation is poorly understood. Expression of NIK was analyzed by quantitative RT-PCR in BCSCs. NIK levels were manipulated through transfection of specific shRNAs or an expression vector. The effect of NIK in the cancer stem cell properties was assessed by mammosphere formation, mice xenografts and stem markers expression. BCSCs expressed higher levels of NIK and its inhibition through small hairpin (shRNA), reduced the expression of CSC markers and impaired clonogenicity and tumorigenesis. Genome-wide expression analyses suggested that NIK acts on ERK1/2 pathway to exert its activity. In addition, forced expression of NIK increased the BCSC population and enhanced breast cancer cell tumorigenicity. The in vivo relevance of these results is further supported by a tissue microarray of breast cancer samples in which we observed correlated expression of Aldehyde dehydrogenase (ALDH) and NIK protein. Our results support the essential involvement of NIK in BCSC phenotypic regulation via ERK1/2 and NF-κB.
authors.affiliation: Instituto Nacional de Medicina Genómica (INMEGEN), México, 14610, México.
authors.forename: Karla
authors.initials: K
authors.lastname: Vazquez-Santillan
authors.affiliation: Instituto Nacional de Medicina Genómica (INMEGEN), México, 14610, México.
authors.forename: Jorge
authors.initials: J
authors.lastname: Melendez-Zajgla
authors.affiliation: Instituto Nacional de Medicina Genómica (INMEGEN), México, 14610, México.
authors.forename: Luis Enrique
authors.initials: LE
authors.lastname: Jimenez-Hernandez
authors.affiliation: Instituto Nacional de Medicina Genómica (INMEGEN), México, 14610, México.
authors.forename: Javier
authors.initials: J
authors.lastname: Gaytan-Cervantes
authors.affiliation: Instituto Nacional de Medicina Genómica (INMEGEN), México, 14610, México.
authors.forename: Laura
authors.initials: L
authors.lastname: Muñoz-Galindo
authors.affiliation: Unidad de Investigación Médica en Enfermedades Oncológicas (UIMEO), Hospital de Oncología IMSS, México.
authors.forename: Patricia
authors.initials: P
authors.lastname: Piña-Sanchez
authors.affiliation: Instituto Nacional de Medicina Genómica (INMEGEN), México, 14610, México.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Martinez-Ruiz
authors.affiliation: Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias (UMAE), Hospital de Pediatría, IMSS, México.
authors.forename: Javier
authors.initials: J
authors.lastname: Torres
authors.affiliation: Instituto Nacional de Cancerología (INCAN), México.
authors.forename: Patricia
authors.initials: P
authors.lastname: Garcia-Lopez
authors.affiliation: Instituto Nacional de Medicina Genómica (INMEGEN), México, 14610, México.
authors.forename: Carolina
authors.initials: C
authors.lastname: Gonzalez-Torres
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias "Ismael Cosío Villegas" (INER), México.
authors.forename: Victor
authors.initials: V
authors.lastname: Ruiz
authors.affiliation: Facultad de Estudios Superiores Iztacala, UNAM, México.
authors.forename: Federico
authors.initials: F
authors.lastname: Avila-Moreno
authors.affiliation: Facultad de Medicina UNAM, México.
authors.forename: Marco
authors.initials: M
authors.lastname: Velasco-Velazquez
authors.affiliation: Unidad de Desarrollo e Investigación en Bioprocesos (UDIBI) y Departamento de Inmunología, IPN, México.
authors.forename: Mayra
authors.initials: M
authors.lastname: Perez-Tapia
authors.affiliation: Instituto Nacional de Medicina Genómica (INMEGEN), México, 14610, México.
authors.forename: Vilma
authors.initials: V
authors.lastname: Maldonado
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics; D014183:Transplantation, Heterologous; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase