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

Lindsay Bennett, Elizabeth A Mallon, Paul G. Horgan, Andrew Paul, Donald C. McMillan, Joanne Edwards

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

LanguageEnglish
Pages33002-33013
Number of pages12
JournalOncotarget
Volume8
Issue number20
DOIs
Publication statusPublished - 9 Mar 2017

Fingerprint

Tumor Microenvironment
Breast Neoplasms
Survival
Neoplasms
Cell Survival
Apoptosis
MCF-7 Cells
Small Interfering RNA
Transfection
Phosphotransferases
Multivariate Analysis
Western Blotting
Immunohistochemistry
Cell Line

Keywords

  • breast cancer
  • NF-κB
  • survival
  • tumour microenvironment

Cite this

Bennett, Lindsay ; Mallon, Elizabeth A ; Horgan, Paul G. ; Paul, Andrew ; McMillan, Donald C. ; Edwards, Joanne. / The relationship between members of the canonical NF-κB pathway, components of tumour microenvironment and survival in patients with invasive ductal breast cancer. In: Oncotarget. 2017 ; Vol. 8, No. 20. pp. 33002-33013.
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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; Mallon, Elizabeth A; Horgan, Paul G.; Paul, Andrew; McMillan, Donald C.; Edwards, Joanne.

In: Oncotarget, Vol. 8, No. 20, 09.03.2017, p. 33002-33013.

Research output: Contribution to journalArticle

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