Hierarchical clustering of immunohistochemical analysis of the activated ErbB/PI3K/Akt/NF-κB signalling pathway and prognostic significance in prostate cancer

Abstract

Background:The PI3K/Akt signalling pathway, induced by epidermal growth factor receptor (EGFR) and Her-2, is involved in the constitutive activation of NF-κB in prostate cancer cell lines. In this study, we extended the in vitro observation using an ex vivo model of prostate cancer tissues and assessed the prognostic significance of the PI3K/Ak/NF-κB signalling determinants.Methods:We analysed a prostate cancer tissue microarray of 63 patients for the expression of total and activated EGFR, Her-2 receptors and the signalling molecules PTEN, phospho-PTEN, Akt, phospho-Akt and the NF-κB subunit p65. Data were analysed using Spearman's rho test, Kaplan–Meier curves and multivariate Cox regression analysis. In addition, a non-supervised hierarchical clustering analysis was applied to stratify patients according to prognostic groups in terms of risk of recurrence.Results:The concomitant overexpression of activated EGFR and Her-2 was correlated with the nuclear expression of NF-κB. EGFR, phospho-EGFR, phospho-Her-2, ErbB3 and nuclear NF-κB were associated with the overall biochemical recurrence (BCR) of patients. The non-supervised hierarchical clustering analysis resulted in the separation of patients into five groups according to BCR.Conclusions:These results validate the previous in vitro data on ErbB involvement in NF-κB activation and shows evidence for a significant role of ErbB/PI3K/Akt/NF-κB signalling in the progression of prostate cancer.