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NF-kappa Β -inducing kinase regulates stem cell phenotype in breast cancer

View Article: PubMed Central - PubMed

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.

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NIK is expressed mainly in the Human epithelial growth factor receptor (HER2) subtype.(A) Pie chart showing the percentage of HER2, Luminal, and Triple Negative breast cancer samples (n = 191). (B) Percentage of cells expressing NIK in HER2, Luminal, and Triple Negative breast tumors. NIK expression is higher in HER2 breast tumors (p = 0.01). (C) Percentage of cells expressing NIK in tumors with different expression levels of HER2 (0 = absent; 1 = weak; 2 = moderate; 3 = strong). NIK expression is higher in tumors with strong expression of HER2 (p = 0.005). (D) Pie chart showing the percentage of Grades I, II, and III breast cancer tissues (n = 191). (E) Percentage of cells expressing NIK in Grade I, II and III tumors. NIK expression levels increase in Grade III tumor (p = 0.07).
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f6: NIK is expressed mainly in the Human epithelial growth factor receptor (HER2) subtype.(A) Pie chart showing the percentage of HER2, Luminal, and Triple Negative breast cancer samples (n = 191). (B) Percentage of cells expressing NIK in HER2, Luminal, and Triple Negative breast tumors. NIK expression is higher in HER2 breast tumors (p = 0.01). (C) Percentage of cells expressing NIK in tumors with different expression levels of HER2 (0 = absent; 1 = weak; 2 = moderate; 3 = strong). NIK expression is higher in tumors with strong expression of HER2 (p = 0.005). (D) Pie chart showing the percentage of Grades I, II, and III breast cancer tissues (n = 191). (E) Percentage of cells expressing NIK in Grade I, II and III tumors. NIK expression levels increase in Grade III tumor (p = 0.07).

Mentions: Finally, we determined NIK levels in 191 breast cancer tissue samples of which 60.7% were Luminal, 13.6% were triple negative and 9.4% were HER2 breast cancer subtype (Fig. 6A). To determine whether NIK expression is related to a particular breast cancer subtype, we examine NIK expression by immunohistochemistry, and we found that NIK expression was significantly higher in HER2+ breast carcinomas (Fig. 6B), and the expression of NIK positively correlated with HER2 expression levels (Fig. 6C). We also found that Triple Negative carcinomas exhibited the lowest expression of NIK, contrary to previous reports of breast cancer cell lines (Fig. 6B). Tumor Samples were also classified as grade 1, 2 and 3 (Fig. 6D). Interestingly, we observed a clear positive association between NIK and tumor grade (Fig. 6E).


NF-kappa Β -inducing kinase regulates stem cell phenotype in breast cancer
NIK is expressed mainly in the Human epithelial growth factor receptor (HER2) subtype.(A) Pie chart showing the percentage of HER2, Luminal, and Triple Negative breast cancer samples (n = 191). (B) Percentage of cells expressing NIK in HER2, Luminal, and Triple Negative breast tumors. NIK expression is higher in HER2 breast tumors (p = 0.01). (C) Percentage of cells expressing NIK in tumors with different expression levels of HER2 (0 = absent; 1 = weak; 2 = moderate; 3 = strong). NIK expression is higher in tumors with strong expression of HER2 (p = 0.005). (D) Pie chart showing the percentage of Grades I, II, and III breast cancer tissues (n = 191). (E) Percentage of cells expressing NIK in Grade I, II and III tumors. NIK expression levels increase in Grade III tumor (p = 0.07).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120353&req=5

f6: NIK is expressed mainly in the Human epithelial growth factor receptor (HER2) subtype.(A) Pie chart showing the percentage of HER2, Luminal, and Triple Negative breast cancer samples (n = 191). (B) Percentage of cells expressing NIK in HER2, Luminal, and Triple Negative breast tumors. NIK expression is higher in HER2 breast tumors (p = 0.01). (C) Percentage of cells expressing NIK in tumors with different expression levels of HER2 (0 = absent; 1 = weak; 2 = moderate; 3 = strong). NIK expression is higher in tumors with strong expression of HER2 (p = 0.005). (D) Pie chart showing the percentage of Grades I, II, and III breast cancer tissues (n = 191). (E) Percentage of cells expressing NIK in Grade I, II and III tumors. NIK expression levels increase in Grade III tumor (p = 0.07).
Mentions: Finally, we determined NIK levels in 191 breast cancer tissue samples of which 60.7% were Luminal, 13.6% were triple negative and 9.4% were HER2 breast cancer subtype (Fig. 6A). To determine whether NIK expression is related to a particular breast cancer subtype, we examine NIK expression by immunohistochemistry, and we found that NIK expression was significantly higher in HER2+ breast carcinomas (Fig. 6B), and the expression of NIK positively correlated with HER2 expression levels (Fig. 6C). We also found that Triple Negative carcinomas exhibited the lowest expression of NIK, contrary to previous reports of breast cancer cell lines (Fig. 6B). Tumor Samples were also classified as grade 1, 2 and 3 (Fig. 6D). Interestingly, we observed a clear positive association between NIK and tumor grade (Fig. 6E).

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus