Regulation of breast cancer induced bone disease by cancer-specific IKKβ
Bibliographic record
Abstract
// Silvia Marino 1, 2 , Ryan T. Bishop 1 , Mattia Capulli 6 , Antonia Sophocleous 3 , John G Logan 2, 3 , Patrick Mollat 5 , Barbara Mognetti 4 , Luca Ventura 7 , Andrew H. Sims 8 , Nadia Rucci 6 , Stuart H. Ralston 3 and Aymen I. Idris 1, 2 1 Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK 2 Bone and Cancer Group, Edinburgh Cancer Research Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK 3 Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK 4 University of Turin, Department of Clinical and Biological Sciences, Orbassano, Italy 5 Galapagos SASU, Romainville, France 6 University of L’Aquila, Department of Biotechnological and Applied Clinical Sciences, L’Aquila, Italy 7 Department of Pathology, San Salvatore Hospital, L’Aquila, Italy 8 Applied Bioinformatics of Cancer, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK Correspondence to: Aymen I. Idris, email: aymen.idris@sheffield.ac.uk Keywords: IKKβ; NFκB; breast cancer; bone metastasis; osteolysis Received: November 08, 2017 Accepted: February 25, 2018 Published: March 23, 2018 ABSTRACT 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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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".