Nuclear Factor-κB Nuclear Localization Is Predictive of Biochemical Recurrence in Patients with Positive Margin Prostate Cancer

Abstract

Purpose: Radical prostatectomy (RP) patients with positive surgical margins are at increased risk for recurrence, emphasizing the need for prognostic markers to stratify probable outcome for optimal patient management decisions. We tested the hypothesis that nuclear localization of nuclear factor (NF)-B, a transcription factor involved in the regulation of cell growth, angiogenesis, invasion, and apoptosis, is associated with an increased risk of biochemical recurrence after RP.Experimental Design: Analyses addressed data from 42 patients (age range, 52-72 years; mean age, 63.7 years) who exhibited positive surgical margins after RP. Immunohistochemical analysis of NF-B (p65) was performed on the positive margin tissue. A nuclear staining cutoff of >5% was considered positive. The relation between nuclear NF-B expression and biochemical recurrence (prostate-specific antigen >0.3 ng/mL and rising) after RP was tested in univariate and multivariate Cox regression models.Results: Biochemical recurrence was recorded in 23 patients (54.8%; median follow-up, 3.2 years). Univariate Cox regression demonstrated a 4.9-fold (95% confidence interval, 1.5-16.7; P ‫؍‬ 0.01) higher rate of recurrence in men with NF-B > 5%. In the multivariate model, after controlling for primary (P ‫؍‬ 0.004) and secondary (P ‫؍‬ 0.7) Gleason patterns, lymph node (P ‫؍‬ 0.06) and seminal vesicle invasion (P ‫؍‬ 0.2), and preoperative prostate-specific antigen (P ‫؍‬ 0.009), NF-B > 5% was associated with a 6.2-fold higher risk of biochemical recurrence (95% confidence interval, 1.7-23.5; P ‫؍‬ 0.007).Conclusions: In univariate and multivariate analysis, NF-B nuclear expression was strongly predictive of biochemical recurrence in patients with positive surgical margins after RP. We propose that nuclear NF-B may serve as a useful independent molecular marker for stratifying patients at risk for recurrence.

Activation of nuclear factor-κB in human prostate carcinogenesis and association to biochemical relapse

“…However, NF-kB nuclear localisation was unrelated to the risk of biochemical relapse (Ross et al, 2004). Notably, the rate of nuclear NF-kB staining (15%) in the study by Ross et al was lower than what we report in the present study (54.7%) or other reports (Fradet et al, 2004). We showed that the antibody used in the present work detected nuclear translocation (activation) of NF-kB/p65 under controlled experimental cell culture conditions.…”

“…Of note in this study was the fact that nuclear NF-kB expression was not specifically linked with disease relapse. However, in another study performed in patients with prostate cancer and pathologically positive surgical margins in the prostatectomy specimens, NF-kB nuclear localisation was associated to a high risk of biochemical relapse (Fradet et al, 2004).…”

“…Along this line, several preclinical observations have shown that NF-kB plays a role in prostate cancer growth, survival, angiogenesis and metastatic progression (Muenchen et al, 2000;Yu et al, 2000;Catz and Johnson, 2001;Huang et al, 2001;Gasparian et al, 2002;Gunawardena et al, 2002;Gupta et al, 2002;Suh et al, 2002;Zerbini et al, 2003;Suh and Rabson, 2004). Furthermore, emerging data obtained from human studies also suggest a potential role of NF-kB in prostate cancer tumorigenesis and/or in its behaviour in a clinical setting (Suh et al, 2002;Lessard et al, 2003;Fradet et al, 2004;Ismail et al, 2004;Ross et al, 2004). In particular, a recent study showed that total overexpression of p65, the best characterised NF-kB protein, was an independent predictor of poor prognosis in prostate cancer patients (Ross et al, 2004).…”

High expression of RelA/p65 is associated with activation of nuclear factor-κB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis

“…The prognostic value of RelA is in concordance with studies on prostate cancer, in which both nuclear and cytoplasmic RelA overexpression were linked to disease progression (Fradet et al, 2004;Ross et al, 2004). In gastric adenocarcinoma, the prognostic impact of RelA expression appears to be somewhat conflictive, as overexpression was reported both to be an indicator of adverse (Sasaki et al, 2001;Yamanaka et al, 2004) and favourable (Lee et al, 2005) patient prognosis.…”

“…Here, we found the NF-kB subunit RelA to be overexpressed in roughly half of a large set of pancreatic adenocarcinomas analysed. Overexpression of cytoplasmic and/or nuclear RelA in tumour tissue has been previously observed in larger study cohorts of gastric (Sasaki et al, 2001;Yamanaka et al, 2004;Cao et al, 2005;Lee et al, 2005), prostate (Fradet et al, 2004;Ismail et al, 2004;Ross et al, 2004; Figure 2 Kaplan -Meier survival curves in dependence of clinicopathological factors and RelA/p65 expression patterns. Overall survival dependent on nodal status (A) and grade (B).…”