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Open Access Research article

NF-kappaB activation within macrophages leads to an anti-tumor phenotype in a mammary tumor lung metastasis model

Linda Connelly12, Whitney Barham1, Halina M Onishko1, Lianyi Chen1, Taylor P Sherrill3, Tahera Zabuawala4, Michael C Ostrowski4, Timothy S Blackwell135 and Fiona E Yull1*

Author Affiliations

1 Department of Cancer Biology, Vanderbilt University, 771 Preston Research Building, 2220 Pierce Avenue, Nashville, TN 37232, USA

2 Department of Pharmaceutical Sciences, UH Hilo College of Pharmacy, University of Hawaii at Hilo, 200 W. Kawili Street, Hilo, HI 96720, USA

3 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University, T-1217 Medical Center North, Nashville, TN 37232, USA

4 Department of Molecular and Cellular Biochemistry, The Comprehensive Cancer Center, Ohio State University, 810 Biomedical Research Tower, 460 W. 12th Avenue, Columbus, OH 43210, USA

5 Department of Veterans Affairs, T-1217 Medical Center North, Nashville, TN 37232, USA

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Breast Cancer Research 2011, 13:R83  doi:10.1186/bcr2935

Published: 31 August 2011

Abstract

Introduction

Metastasis from primary tumor to the lungs is a major cause of the mortality associated with breast cancer. Both immune and inflammatory responses impact whether circulating mammary tumor cells successfully colonize the lungs leading to established metastases. Nuclear factor -kappaB (NF-κB) transcription factors regulate both immune and inflammatory responses mediated in part by the activities of macrophages. Therefore, NF-κB activity specifically within macrophages may be a critical determinant of whether circulating tumor cells successfully colonize the lungs.

Methods

To investigate NF-κB signaling within macrophages during metastasis, we developed novel inducible transgenic models which target expression of the reverse tetracycline transactivator (rtTA) to macrophages using the cfms promoter in combination with inducible transgenics that express either an activator (cIKK2) or an inhibitor (IκBα-DN). Doxycyline treatment led to activation or inhibition of NF-κB within macrophages. We used a tail vein metastasis model with mammary tumor cell lines established from MMTV-Polyoma Middle T-Antigen-derived tumors to investigate the effects of modulating NF-κB in macrophages during different temporal windows of the metastatic process.

Results

We found that activation of NF-κB in macrophages during seeding leads to a reduction in lung metastases. The mechanism involved expression of inflammatory cytokines and reactive oxygen species, leading to apoptosis of tumor cells and preventing seeding in the lung. Activation of NF-κB within macrophages after the seeding phase has no significant impact on establishment of metastases.

Conclusions

Our results have identified a brief, defined window in which activation of NF-κB has significant anti-metastatic effects and inhibition of NF-κB results in a worse outcome.