title: Interleukin-1beta and fibroblast growth factor receptor 1 cooperate to induce cyclooxygenase-2 during early mammary tumourigenesis.
abstract: BACKGROUND
  Inflammation within the tumour microenvironment correlates with increased invasiveness and poor prognosis in many types of cancer, including breast cancer. We have previously demonstrated that activation of a mouse mammary tumour virus (MMTV)-driven inducible fibroblast growth factor receptor 1 (iFGFR1) transgene in mammary epithelial cells results in an inflammatory response characterised by induction of inflammatory genes in the mammary gland. Specifically, we have observed increased levels of IL-1beta expression in the mammary gland following activation of iFGFR1 and have used the iFGFR1 model to elucidate the function of IL-1beta in promoting iFGFR1-induced mammary lesions.
  
  
  METHODS
  To determine the functional consequences of IL-1beta induction during FGFR1-induced mammary tumourigenesis, the effects of IL-1beta inhibition on the formation of epithelial hyperplasias were examined using the MMTV-iFGFR1 transgenic mouse model. Further studies used a combination of the HC-11 mammary epithelial cell line that stably expresses iFGFR1 and the MMTV-iFGFR1 transgenic mice to further define the mechanisms of IL-1beta function.
  
  
  RESULTS
  Inhibition of IL-1beta activity in vivo resulted in reduced iFGFR1-induced epithelial proliferation and formation of hyperplastic structures. Further studies demonstrated that treatment of mammary epithelial cells with IL-1beta-induced expression of cyclooxygenase (Cox)-2 both in vitro and in vivo. Finally, inhibition of Cox-2 prior to activation of iFGFR1 in the transgenic mice also resulted in decreased iFGFR1-induced formation of hyperplastic structures.
  
  
  CONCLUSIONS
  The results from these studies indicate that targeting the inflammatory cytokine IL-1beta partially inhibits iFGFR1-induced formation of early-stage mammary lesions, in part through induction of Cox-2. These findings demonstrate that activation of a growth factor receptor in mammary epithelial cells results in increased expression of inflammatory mediators, which cooperate to promote the initiation of hyperplastic lesions in the mammary gland.
authors.affiliation: Microbiology, Immunology and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Johanna R
authors.initials: JR
authors.lastname: Reed
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Leon
authors.forename: Majken K
authors.initials: MK
authors.lastname: Hall
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Schwertfeger
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006965:Hyperplasia; D007124:Immunoenzyme Techniques; D053583:Interleukin-1beta / Q000502:physiology*; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D012333:RNA, Messenger; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1