title: NF-kappaB activation within macrophages leads to an anti-tumor phenotype in a mammary tumor lung metastasis model.
abstract: BACKGROUND
  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.
authors: Department of Cancer Biology, Vanderbilt University, 771 Preston Research Building, 2220 Pierce Avenue, Nashville, TN 37232, USA.
authors: Linda
authors: L
authors: Connelly
authors: Whitney
authors: W
authors: Barham
authors: Halina M
authors: HM
authors: Onishko
authors: Lianyi
authors: L
authors: Chen
authors: Taylor P
authors: TP
authors: Sherrill
authors: Tahera
authors: T
authors: Zabuawala
authors: Michael C
authors: MC
authors: Ostrowski
authors: Timothy S
authors: TS
authors: Blackwell
authors: Fiona E
authors: FE
authors: Yull
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D005260:Female; D005467:Floxuridine / Q000494:pharmacology; D051550:I-kappa B Kinase / Q000235:genetics; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000556:secondary*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010641:Phenotype; D011120:Polyomavirus / Q000472:pathogenicity; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species; D016184:Receptors, Colony-Stimulating Factor / Q000235:genetics; D015398:Signal Transduction; D014680:Veins / Q000821:virology
chemical_list: D039481:CD11b Antigen; D054370:Chemokine CXCL9; C485969:Cxcl9 protein, mouse; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D016184:Receptors, Colony-Stimulating Factor; D005467:Floxuridine; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C025034:doxifluridine