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Sci Rep. 2016 Nov 23;6:37340. doi: 10.1038/srep37340.

NF-kappaΒ-inducing kinase regulates stem cell phenotype in breast cancer.

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Instituto Nacional de Medicina Genómica (INMEGEN), México, 14610, México.
Unidad de Investigación Médica en Enfermedades Oncológicas (UIMEO), Hospital de Oncología IMSS, México.
Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias (UMAE), Hospital de Pediatría, IMSS, México.
Instituto Nacional de Cancerología (INCAN), México.
Instituto Nacional de Enfermedades Respiratorias "Ismael Cosío Villegas" (INER), México.
Facultad de Estudios Superiores Iztacala, UNAM, México.
Facultad de Medicina UNAM, México.
Unidad de Desarrollo e Investigación en Bioprocesos (UDIBI) y Departamento de Inmunología, IPN, México.


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.

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