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.

• Authors: Rachel Eyre, Denis G Alférez, Angélica Santiago-Gómez, Kath Spence, James C McConnell, Claire Hart, Bruno M Simões, Diane Lefley, Claudia Tulotta, Joanna Storer, Austin Gurney, Noel Clarke, Mick Brown, Sacha J Howell, Andrew H Sims, Gillian Farnie, Penelope D Ottewell, Robert B Clarke
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 5016 (11 01 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 31676788 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• IL1B protein, human
• Interleukin-1beta
• Sulfasalazine

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Bone Neoplasms (drug therapy, metabolism, secondary)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Female
• HEK293 Cells
• Humans
• Interleukin-1beta (metabolism)
• MCF-7 Cells
• Mice, Inbred BALB C
• Mice, Inbred NOD
• Mice, Knockout
• Mice, Nude
• Mice, SCID
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Sulfasalazine (administration & dosage)
• Tumor Microenvironment (drug effects)
• Wnt Signaling Pathway
• Xenograft Model Antitumor Assays