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Cancer Res. 2017 Dec 15;77(24):6927-6940. doi: 10.1158/0008-5472.CAN-17-0366. Epub 2017 Oct 26.

NFκB Promotes Ovarian Tumorigenesis via Classical Pathways That Support Proliferative Cancer Cells and Alternative Pathways That Support ALDH+ Cancer Stem-like Cells.

Author information

1
Women's Malignancies Branch, National Cancer Institute, Bethesda, Maryland.
2
Experimental Immunology Branch, National Cancer Institute, Bethesda, Maryland.
3
Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland.
4
Collaborative Bioinformatics Resource, National Cancer Institute, Bethesda, Maryland.
5
Women's Malignancies Branch, National Cancer Institute, Bethesda, Maryland. annunzic@mail.nih.gov.

Abstract

Understanding the mechanisms supporting tumor-initiating cells (TIC) is vital to combat advanced-stage recurrent cancers. Here, we show that in advanced ovarian cancers NFκB signaling via the RelB transcription factor supports TIC populations by directly regulating the cancer stem-like associated enzyme aldehyde dehydrogenase (ALDH). Loss of RelB significantly inhibited spheroid formation, ALDH expression and activity, chemoresistance, and tumorigenesis in subcutaneous and intrabursal mouse xenograft models of human ovarian cancer. RelB also affected expression of the ALDH gene ALDH1A2 Interestingly, classical NFκB signaling through the RelA transcription factor was equally important for tumorigenesis in the intrabursal model, but had no effect on ALDH. In this case, classical signaling via RelA was essential for proliferating cells, whereas the alternative signaling pathway was not. Our results show how NFκB sustains diverse cancer phenotypes via distinct classical and alternative signaling pathways, with implications for improved understanding of disease recurrence and therapeutic response. Cancer Res; 77(24); 6927-40. ©2017 AACR.

PMID:
29074539
PMCID:
PMC5732863
DOI:
10.1158/0008-5472.CAN-17-0366
[Indexed for MEDLINE]
Free PMC Article

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