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Inhibition of NF-kappa B activity in mammary epithelium increases tumor latency and decreases tumor burden

Oncogene volume 30, pages 1402–1412 (2011)Cite this article

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Abstract

The transcription factor nuclear factor kappa B (NF-κB) is activated in human breast cancer tissues and cell lines. However, it is unclear whether NF-κB activation is a consequence of tumor formation or a contributor to tumor development. We developed a doxycycline (dox)-inducible mouse model, termed DNMP, to inhibit NF-κB activity specifically within the mammary epithelium during tumor development in the polyoma middle T oncogene (PyVT) mouse mammary tumor model. DNMP females and PyVT littermate controls were treated with dox from 4 to 12 weeks of age. We observed an increase in tumor latency and a decrease in final tumor burden in DNMP mice compared with PyVT controls. A similar effect with treatment from 8 to 12 weeks indicates that outcome is independent of effects on postnatal virgin ductal development. In both cases, DNMP mice were less likely to develop lung metastases than controls. Treatment from 8 to 9 weeks was sufficient to impact primary tumor formation. Inhibition of NF-κB increases apoptosis in hyperplastic stages of tumor development and decreases proliferation at least in part by reducing Cyclin D1 expression. To test the therapeutic potential of NF-κB inhibition, we generated palpable tumors by orthotopic injection of PyVT cells and then treated systemically with the NF-κB inhibitor thymoquinone (TQ). TQ treatment resulted in a reduction in tumor volume and weight as compared with vehicle-treated control. These data indicate that epithelial NF-κB is an active contributor to tumor progression and demonstrate that inhibition of NF-κB could have a significant therapeutic impact even at later stages of mammary tumor progression.

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Acknowledgements

This work was supported by NIH grant CA113734 awarded to FE Yull and a US Department of Veterans Affairs grant awarded to TS Blackwell.

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Authors and Affiliations

  1. Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA

    L Connelly, W Barham, H M Onishko, T S Blackwell & F E Yull

  2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Hawaii at Hilo, Hilo, HI, USA

    L Connelly

  3. Department of Medicine, Vanderbilt University, Nashville, TN, USA

    T Sherrill & T S Blackwell

  4. Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA

    L A Chodosh

  5. Department of Veterans Affairs, Nashville, TN, USA

    T S Blackwell

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  1. L Connelly
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Correspondence to F E Yull.

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Connelly, L., Barham, W., Onishko, H. et al. Inhibition of NF-kappa B activity in mammary epithelium increases tumor latency and decreases tumor burden. Oncogene 30, 1402–1412 (2011). https://doi.org/10.1038/onc.2010.521

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  • DOI: https://doi.org/10.1038/onc.2010.521

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