The relationship between members of the canonical NF-KB pathway, components of tumour microenvironment and survival in patients with invasive ductal breast cancer

Bennett, L., Mallon, E. A., Horgan, P. G. , Paul, A., McMillan, D. C. and Edwards, J. (2017) The relationship between members of the canonical NF-KB pathway, components of tumour microenvironment and survival in patients with invasive ductal breast cancer. Oncotarget, 8(20), pp. 33002-33013. (doi: 10.18632/oncotarget.16031) (PMID:28423692)

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Abstract

The aim of the present study was to examine the relationship between tumour NF-κB activation, tumour microenvironment including local inflammatory response (LIR) and cancer-specific survival in patients with operable ductal breast cancer. Immunohistochemistry (tissue microarray of 376 patients) and western blotting (MCF7 and MDA-MB-231 breast cancer cells) was performed to assess expression of key members of the canonical NF-κB pathway (inhibitory kappa B kinase (IKKβ) and phosphorylated p65 Ser-536 (p-p65)). Following silencing of IKKβ, cell viability and apoptosis was assessed in both MCF7 and MDA-MB-231 cell lines. P-p65 was associated with cancer-specific survival (CSS) (nuclear P=0.042 and total P=0.025). High total p-p65 was associated with increase grade tumour grade (P=0.010), ER positivity (P=0.023), molecular subtype (P=0.005), lower Klintrup-Makinen grade (P=0.013) and decreased CD138 count (P=0.032). On multivariate analysis, total p-p65 expression independently associated with poorer CSS (P=0.020). In vitro work demonstrated that the canonical NF-κB pathway was inducible by exposure to TNFα in ER-positive MCF7 cells and to a lesser extent in ER-negative MDA-MB-231 cells. Reduction of IKKβ expression by siRNA transfection increased levels of apoptosis and reduced cell viability in both MCF7 (P=<0.001, P=<0.001, respectively) and MDA-MB-231 cells (P=>0.001, P=0.002, respectively). This is consistent with the hypothesis that canonical IKKβ-NF-κB signalling drives tumour survival. These results suggest that activation of the canonical NF-κB pathway is an important determinant of poor outcome in patients with invasive ductal breast cancer.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Horgan, Professor Paul and Bennett, Miss Lindsay and McMillan, Professor Donald and Mallon, Dr Elizabeth and Edwards, Professor Joanne
Authors: Bennett, L., Mallon, E. A., Horgan, P. G., Paul, A., McMillan, D. C., and Edwards, J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Oncotarget
Publisher:Impact Journals
ISSN:1949-2553
ISSN (Online):1949-2553
Published Online:09 March 2017
Copyright Holders:Copyright © 2017 Bennett et al.
First Published:First published in Oncotarget 8(20): 33002-33013
Publisher Policy:Reproduced under a Creative Commons License

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