title: IL-1 drives breast cancer growth and bone metastasis in vivo.
abstract: BACKGROUND
  We have recently identified interleukin 1B (IL-1B) as a potential biomarker for predicting breast cancer patients at increased risk for developing bone metastasis. In mouse models, IL-1B and its receptor (IL-1R1) are upregulated in breast cancer cells that metastasise to bone compared with cells that do not. We have now investigated the functional role of IL-1 by blocking IL-1R signalling with the clinically licensed antagonist, anakinra.
  
  
  METHODS
  6-week old female BALB/c mice received a subcutaneous or intra-venous injection of MDA-MB-231-IV or MCF7 cells. Anakinra (1mg/kg/day) or placebo was administered 3 days before (preventative) or 7 days later (treatment). Tumour volume, apoptosis (TUNEL, Caspase 3), proliferation (Ki67) and angiogenesis (CD34, VEGF and endothelin) were analysed. Effects on bone were measured by uCT, and TRAP, P1NP, IL-1B, TNF alpha and IL-6 ELISA.
  
  
  RESULTS
  Anakinra significantly reduced growth of MDA-MB-231-IV tumours in bone from 6.50+/3.00mm2 (placebo) to 2.56+/-1.07mm2 (treatment) and 0.63+/-0.18mm2 (preventative). Anakinra also reduced the number of mice that developed bone metastasis from 90% (placebo) to 40% (treatment) and 10% (preventative). Anti-tumour effects were not confined to bone, subcutaneous tumour volumes reduced from 656.68mm3 (placebo) to 160.47mm3 (treatment) and 31.08mm3 (preventative). Anakinra did not increase tumour cell apoptosis but reduced proliferation and angiogenesis in addition to exerting significant effects on the tumour environment reducing bone turnover markers, IL-1B and TNF alpha.
  
  
  CONCLUSIONS
  Our novel data demonstrate a functional role of IL-1 signalling in breast tumour progression and metastasis, supporting that anakinra could be repurposed for the treatment of breast cancer bone metastasis.
authors.affiliation: Academic Unit of Clinical Oncology, Department of Oncology and Metabolism, Mellanby Centre for Bone Research, University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Ingunn
authors.initials: I
authors.lastname: Holen
authors.affiliation: Academic Unit of Clinical Oncology, Department of Oncology and Metabolism, Mellanby Centre for Bone Research, University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Diane V
authors.initials: DV
authors.lastname: Lefley
authors.affiliation: Department of Infection Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Sheila E
authors.initials: SE
authors.lastname: Francis
authors.affiliation: Academic Unit of Clinical Oncology, Department of Oncology and Metabolism, Mellanby Centre for Bone Research, University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Rennicks
authors.affiliation: Academic Unit of Clinical Oncology, Department of Oncology and Metabolism, Mellanby Centre for Bone Research, University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Bradbury
authors.affiliation: Academic Unit of Clinical Oncology, Department of Oncology and Metabolism, Mellanby Centre for Bone Research, University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Coleman
authors.affiliation: Academic Unit of Clinical Oncology, Department of Oncology and Metabolism, Mellanby Centre for Bone Research, University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Penelope
authors.initials: P
authors.lastname: Ottewell
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000556:secondary*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D060833:Cellular Microenvironment; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism*; D051379:Mice; D047368:Tumor Burden
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1
keywords: IL-1B; IL-1R; anakinra; bone metastasis; breast cancer