The relationship between members of the canonical NF-κB pathway, components of tumour microenvironment and survival in patients with invasive ductal breast cancer
Bennett, Lindsay and Mallon, Elizabeth A and Horgan, Paul G. and Paul, Andrew and McMillan, Donald C. and Edwards, Joanne (2017) The relationship between members of the canonical NF-κB pathway, components of tumour microenvironment and survival in patients with invasive ductal breast cancer. Oncotarget, 8 (20). pp. 33002-33013. ISSN 1949-2553
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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 MDAMB- 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.
Creators(s): |
Bennett, Lindsay, Mallon, Elizabeth A, Horgan, Paul G., Paul, Andrew ![]() | Item type: | Article |
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ID code: | 61024 |
Keywords: | breast cancer, NF-κB, survival, tumour microenvironment, Neoplasms. Tumors. Oncology (including Cancer), Oncology |
Subjects: | Medicine > Internal medicine > Neoplasms. Tumors. Oncology (including Cancer) |
Department: | Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences |
Depositing user: | Pure Administrator |
Date deposited: | 21 Jun 2017 10:29 |
Last modified: | 12 Feb 2021 03:48 |
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URI: | https://strathprints.strath.ac.uk/id/eprint/61024 |
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