IKK epsilon regulates the breast cancer stem cell phenotype

摘要

The Inhibitor of Nuclear Factor Kappa B Kinase Subunit Epsilon (IKK epsilon) is an oncogenic protein that is up regulated in various types of human cancers, including breast tumors. This kinase regulates diverse processes associated with malignant progression including proliferation, invasion, and metastasis. To delve into the molecular mechanisms regulated by this kinase we performed RNA-seq and network analysis of breast cancer cells overexpressing IKK epsilon. We found that the TNF/NF-kappa B cascade was clearly enriched, and in accordance, NF-kappa B pathway inhibition in these cells resulted in a decreased expression of IKK epsilon target genes. Interestingly, we also found an enrichment of a mammary stemness functional pathway. Upregulation of IKK epsilon led to an increase of a stem CD44+/CD24(-/low) population accompanied by a high expression of stem markers such as ALDH1A3, NANOG, and KLF4 and with an increased clonogenic ability and mammosphere formation capacity. These results were corroborated with in vivo dilution assays in zebrafish embryos which showed a significant increase in the number of Cancer Stem Cells (CSCs). Finally, we found that Triple-Negative breast tumors, which are enriched in CSCs, display higher levels of IKK epsilon than other breast tumors, supporting the association of this kinase with the stem phenotype. In conclusion, our results highlight the role of IKK epsilon kinase in the regulation of the stem cell phenotype in breast cancer cells, as assessed by expression, functional and in vivo assays. These results add to the potential use of this kinase as a therapeutic target in this neoplasia.