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FOXC1 regulates the functions of human basal-like breast cancer cells by activating NF-κB signaling

Oncogene volume 31, pages 4798–4802 (2012)Cite this article

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Abstract

Human basal-like breast cancer (BLBC) is an enigmatic and aggressive malignancy with a poor prognosis. There is an urgent need to identify therapeutic targets for BLBC, because current treatment modalities are limited and not effective. The forkhead box transcription factor FOXC1 has recently been identified as a critical functional biomarker for BLBC. However, how it orchestrates BLBC cells was not clear. Here we show that FOXC1 activates the transcription factor nuclear factor-κB (NF-κB) in BLBC cells by increasing p65/RelA protein stability. High NF-κB activity has been associated with estrogen receptor-negative breast cancer, particularly BLBC. The effect of FOXC1 on p65/RelA protein stability is mediated by increased expression of Pin1, a peptidyl-prolyl isomerase. FOXC1 requires NF-κB for its regulation of cell proliferation, migration and invasion. Notably, FOXC1 overexpression renders breast cancer cells more susceptible to pharmacological inhibition of NF-κB. These results suggest that BLBC cells may rely on FOXC1-driven NF-κB signaling. Interventions of this pathway may provide modalities for the treatment of BLBC.

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Acknowledgements

We thank Yixian Zheng for the HA-ubiquitin plasmid, Fred Miller for 4T1 breast cancer cells, Inder M Verma for IKK double-knockout MEFs, Amer A Beg for p65-null MEFs, and Dave Hoon and Myles Cabot for technical support. This work was supported by National Institutes of Health (CA151610), QVC and the Fashion Footwear Association of New York Charitable Foundation, Associates for Breast & Prostate Cancer Studies, and the Avon Foundation (02-2010-068) to XC.

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Authors and Affiliations

  1. Department of Molecular Oncology, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, CA, USA

    J Wang & X Cui

  2. Department of Surgical Oncology, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, CA, USA

    P S Ray, S P Bagaria & A E Giuliano

  3. Department of Biostatistics, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, CA, USA

    M-S Sim

  4. Department of Medicine, Cancer Biology Program, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    X Z Zhou & K P Lu

  5. Department of Pharmacology and Chemical Biology, Womens Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    A V Lee

  6. Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA

    X Lin

  7. Department of Surgery, Department of Obstetrics and Gynecology, Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    X Cui

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  1. J Wang
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Correspondence to X Cui.

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Competing interests

Dr Wang, Dr Ray, Dr Bagaria and Dr Cui are named inventors on patent applications regarding the role of FOXC1 in cancer.

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Supplementary Information accompanies the paper on the Oncogene website

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Wang, J., Ray, P., Sim, MS. et al. FOXC1 regulates the functions of human basal-like breast cancer cells by activating NF-κB signaling. Oncogene 31, 4798–4802 (2012). https://doi.org/10.1038/onc.2011.635

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  • DOI: https://doi.org/10.1038/onc.2011.635

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