IL-1 drives breast cancer growth and bone metastasis<i>in vivo</i>

Abstract

// Ingunn Holen 1 , Diane V. Lefley 1 , Sheila E. Francis 2 , Sarah Rennicks 1 , Steven Bradbury 1 , Robert E. Coleman 1 , Penelope Ottewell 1 1 Academic Unit of Clinical Oncology, Department of Oncology and Metabolism, Mellanby Centre for Bone Research, University of Sheffield, Sheffield S10 2RX, UK 2 Department of Infection Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2RX, UK Correspondence to: Penelope Ottewell, email: P.D.Ottewell@sheffield.ac.uk Keywords: breast cancer, bone metastasis, IL-1B, IL-1R, anakinra Received: June 01, 2016&emsp;&emsp;&emsp;&emsp; Accepted: September 15, 2016&emsp;&emsp;&emsp;&emsp; Published: September 27, 2016 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. Methodology: 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+/3.00mm 2 (placebo) to 2.56+/-1.07mm 2 (treatment) and 0.63+/-0.18mm 2 (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 656.68mm 3 (placebo) to 160.47mm 3 (treatment) and 31.08mm 3 (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.