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Canonical and non-canonical NF-κB signaling promotes breast cancer tumor-initiating cells

Oncogene volume 33, pages 1297–1305 (2014)Cite this article

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Abstract

Tumor-initiating cells (TICs) are a sub-population of cells that exhibit a robust ability to self-renew and contribute to the formation of primary tumors, the relapse of previously treated tumors and the development of metastases. TICs have been identified in various tumors including those of the breast, and are particularly enriched in the basal-like and claudin-low subtypes of breast cancer. The signaling pathways that contribute to the function and maintenance of TICs are under intense study. We explored the potential involvement of the nuclear factor-κB (NF-κB) family of transcription factors in TICs in cell lines that are representative of basal-like and claudin-low breast cancer. NF-κB was found to be activated in breast cancer cells that form tumorspheres efficiently. Moreover, both canonical and non-canonical NF-κB signaling is required for these cells to self-renew in vitro and to form xenograft tumors efficiently in vivo using limiting dilutions of cells. Consistent with this fact, canonical and non-canonical NF-κB signaling is activated in TICs isolated from breast cancer cell lines. Experimental results indicate that NF-κB promotes the function of TICs by stimulating epithelial-to-mesenchymal transition and by upregulating the expression of the inflammatory cytokines interleukin-1β and interleukin-6. The results suggest the use of NF-κB inhibitors for clinical therapy of certain breast cancers.

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Abbreviations

EMT:

epithelial-to-mesenchymal transition

IκB:

inhibitor of κB

IKK:

IκB kinase

IL:

interleukin

NF-κB:

nuclear factor-κB

TIC:

tumor-initiating cell

TGFβ:

transforming growth factor-β

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Acknowledgements

We would like to thank members of the Baldwin lab for helpful discussions and comments. MFK and JWB were supported by a T32 National Research Service Award (5-T32-CA009156-37) awarded to the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill. MFK was also supported by an F32 National Research Service Award (1F32CA153439-01) from the National Institutes of Health and a post-doctoral Fellowship from the American Cancer Society (120296-PF-11-093-01-DDC). JWB was also supported by an F32 National Research Service Award (1F32CA162628-01) from the National Institutes of Health. Research support was provided by National Cancer Institute, grants CA138937 and CA73756, and by Department of Defense grant BC073048. Additional research support was provided by the Samuel Waxman Cancer Research Foundation.

Author contributions: Dr MFK performed experiments and wrote the manuscript. Dr JWB performed key experiments and edited the manuscript. Dr CLL performed key experiments. KSC performed the tumor xenograft studies. Dr ASB edited the manuscript.

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  1. M F Kendellen

    Present address: 3Current address: Quintiles, Inc., 4820 Emperor Blvd., Durham, NC 27703, USA.,

  2. M F Kendellen and J W Bradford: MFK and JWB are the co-authors.

Authors and Affiliations

  1. Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    M F Kendellen, J W Bradford, C L Lawrence, K S Clark & A S Baldwin

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Kendellen, M., Bradford, J., Lawrence, C. et al. Canonical and non-canonical NF-κB signaling promotes breast cancer tumor-initiating cells. Oncogene 33, 1297–1305 (2014). https://doi.org/10.1038/onc.2013.64

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