Regulation of breast cancer induced bone disease by cancer-specific IKKβ
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Silvia Marino1,2, Ryan T. Bishop1, Mattia Capulli6, Antonia Sophocleous3, John G Logan2,3, Patrick Mollat5, Barbara Mognetti4, Luca Ventura7, Andrew H. Sims8, Nadia Rucci6, Stuart H. Ralston3 and Aymen I. Idris1,2
1Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
2Bone and Cancer Group, Edinburgh Cancer Research Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK
3Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK
4University of Turin, Department of Clinical and Biological Sciences, Orbassano, Italy
5Galapagos SASU, Romainville, France
6University of L’Aquila, Department of Biotechnological and Applied Clinical Sciences, L’Aquila, Italy
7Department of Pathology, San Salvatore Hospital, L’Aquila, Italy
8Applied Bioinformatics of Cancer, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK
Aymen I. Idris, email: firstname.lastname@example.org
Keywords: IKKβ; NFκB; breast cancer; bone metastasis; osteolysis
Received: November 08, 2017 Accepted: February 25, 2018 Published: March 23, 2018
NFκB is implicated in breast cancer bone metastasis and skeletal remodelling. However, the role of IKKβ, a key component of the canonical NFκB pathway, in the regulation of breast cancer osteolytic metastasis has not been investigated. Here, we describe the cancer-specific contribution of IKKβ to bone metastasis, skeletal tumour growth and osteolysis associated with breast cancer. IKKβ is highly expressed in invasive breast tumours and its level of expression was higher in patients with bone metastasis. IKKβ overexpression in parental MDA-MD-231 breast cancer cells, promoted mammary tumour growth but failed to convey osteolytic potential to these cells in mice. In contrast, IKKβ overexpression in osteotropic sub-clones of MDA-MB-231 cells with differing osteolytic phenotypes increased incidence of bone metastasis, exacerbated osteolysis and enhanced skeletal tumour growth, whereas its knockdown was inhibitory. Functional and mechanistic studies revealed that IKKβ enhanced the ability of osteotropic MDA-MB-231 cells to migrate, increase osteoclastogenesis, and to inhibit osteoblast differentiation via a mechanism mediated, at least in part, by cytoplasmic sequestering of FoxO3a and VEGFA production. Thus, tumour-selective manipulation of IKKβ and its interaction with FoxO3a may represent a novel strategy to reduce the development of secondary breast cancer in the skeleton.
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