Hierarchical clustering of immunohistochemical analysis of the activated ErbB/PI3K/Akt/NF-kappaB signalling pathway and prognostic significance in prostate cancer.
BACKGROUND
The PI3K/Akt signalling pathway, induced by epidermal growth factor receptor (EGFR) and Her-2, is involved in the constitutive activation of NF-kappaB 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-kappaB 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-kappaB 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-kappaB. EGFR, phospho-EGFR, phospho-Her-2, ErbB3 and nuclear NF-kappaB 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-kappaB activation and shows evidence for a significant role of ErbB/PI3K/Akt/NF-kappaB signalling in the progression of prostate cancer.
Koumakpayi
I H
IH
Centre de recherche du Centre Hospitalier de l'Université de Montréal and Institut du cancer de Montréal, 1560 rue Sherbrooke est, Montréal, Quebec H2L4M1, Canada.
Le Page
C
C
Mes-Masson
A-M
AM
Saad
F
F
D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D040081:Protein Array Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D015398:Signal Transduction; D050863:Synaptotagmin I / Q000378:metabolism
D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D016328:NF-kappa B; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D050863:Synaptotagmin I; C512478:EGFR protein, human; C508053:ERBB2 protein, human