Expression of nuclear factor-κB and IκBα proteins in prostatic adenocarcinomas:: Correlation of nuclear factor-κB immunoreactivity with disease recurrence

Purpose: The nuclear transcription factor nuclear factor-kappaB (NFkappaB) and its inhibitor, IkappaB, regulate the transcription of various genes involved in cell proliferation, adhesion, and survival. The NFkappaB transcription factor complex plays a role in cancer development and progression through its influence on apoptosis. More recently, NFkappaB has been shown to be activated in human and androgen-independent prostate cancer cells. To our knowledge, this is the first study demonstrating the prognostic significance of NFkappaB immunoreactivity in prostate adenocarcinomas (PACs). Experimental Design: Using prostatectomy specimens, we performed immunohistochemical staining for NFkappaB and IkappaBalpha (Santa Cruz Biotechnology) on formalin-fixed, paraffin-embedded sections obtained from 136 patients with PAC. Cytoplasmic and nuclear immunoreactivity was scored for intensity and distribution, and results were correlated with preoperative serum prostate-specific antigen, tumor grade, stage, DNA ploidy (Feulgen spectroscopy), and biochemical disease recurrence. Results: Forty-nine percent of PACs overexpressed cytoplasmic NFkappaB, and 63% showed decreased IkappaB expression. Cytoplasmic NFkappaB overexpression correlated with advanced tumor stage (P = 0.048), aneuploidy (P = 0.022), and biochemical disease recurrence (P = 0.001). When we compared the means for the NFkappaB-positive and -negative subgroups, NFkappaB overexpression correlated with preoperative serum prostate-specific antigen (P = 0.04) and DNA index (P = 0.05). Fifteen percent of PACs expressed nuclear NFkappaB, which correlated with high tumor grade (P = 0.001) and advanced stage (P = 0.05). Decreased IkappaBalpha expression correlated with high tumor grade (P = 0.015). On multivariate analysis, tumor stage (P = 0.043) and NFkappaB overexpression (P = 0.006) were independent predictors of biochemical recurrence. Conclusion: These results support a role for NFkappaB pathway proteins in the tumorigenesis of PACs. The findings are also consistent with reported experimental studies suggesting a new strategy of combined chemotherapy and specific NFkappaB blockade in decreasing the rate of disease relapse.