Oncotarget

Research Papers:

IL-1 drives breast cancer growth and bone metastasis in vivo

Ingunn Holen, Diane V. Lefley, Sheila E. Francis, Sarah Rennicks, Steven Bradbury, Robert E. Coleman and Penelope Ottewell _

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Oncotarget. 2016; 7:75571-75584. https://doi.org/10.18632/oncotarget.12289

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Abstract

Ingunn Holen1, Diane V. Lefley1, Sheila E. Francis2, Sarah Rennicks1, Steven Bradbury1, Robert E. Coleman1, Penelope Ottewell1

1Academic Unit of Clinical Oncology, Department of Oncology and Metabolism, Mellanby Centre for Bone Research, University of Sheffield, Sheffield S10 2RX, UK

2Department 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    Accepted: September 15, 2016    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+/3.00mm2 (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.


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