Microenvironmental IL1β promotes breast cancer metastatic colonisation in the bone via activation of Wnt signalling

Abstract

Dissemination of tumour cells to the bone marrow is an early event in breast cancer, however cells may lie dormant for many years before bone metastases develop. Treatment for bone metastases is not curative, therefore new adjuvant therapies which prevent the colonisation of disseminated cells into metastatic lesions are required. There is evidence that cancer stem cells (CSCs) within breast tumours are capable of metastasis, but the mechanism by which these colonise bone is unknown. Here, we establish that bone marrow-derived IL1β stimulates breast cancer cell colonisation in the bone by inducing intracellular NFkB and CREB signalling in breast cancer cells, leading to autocrine Wnt signalling and CSC colony formation. Importantly, we show that inhibition of this pathway prevents both CSC colony formation in the bone environment, and bone metastasis. These findings establish that targeting IL1β-NFKB/CREB-Wnt signalling should be considered for adjuvant therapy to prevent breast cancer bone metastasis.

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Item Type:	Article
Authors/Creators:	Eyre, R. Alférez, D.G. Santiago-Gómez, A. Spence, K. McConnell, J.C. Hart, C. Simões, B.M. Lefley, D. Tulotta, C. Storer, J. Gurney, A. Clarke, N. Brown, M. Howell, S.J. Sims, A.H. Farnie, G. Ottewell, P.D. https://orcid.org/0000-0002-4826-0771 Clarke, R.B.
Copyright, Publisher and Additional Information:	© 2019 The Authors. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Accepted: 2 October 2019 Published: 1 November 2019
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Oncology (Sheffield)
Funding Information:	Funder Grant number MEDICAL RESEARCH COUNCIL MR/P000096/1 BREAST CANCER NOW 2016MayPR734 BREAST CANCER NOW R120127 BREAST CANCER NOW R116428 WESTON PARK HOSPITAL CANCER CHARITY CA142
Depositing User:	Symplectic Sheffield
Date Deposited:	18 Nov 2019 15:37
Last Modified:	18 Nov 2019 15:37
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41467-019-12807-0
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:153622

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Microenvironmental IL1β promotes breast cancer metastatic colonisation in the bone via activation of Wnt signalling

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