Nuclear factor κB predicts poor outcome in patients with hormone-naive prostate cancer with high nuclear androgen receptor

Abstract

Despite recent advances in prostate cancer treatments, disease recurrence is common and associated with significant morbidity and mortality. The need for more effective antitumor agents has led researchers to target signaling pathways that drive tumorigenesis by modulating or bypassing androgen receptor signaling--attenuation or blockade of which current treatments aim to effect. The transcription factor nuclear factor κB/p65 has been implicated in prostate cancer progression; however, few studies have examined the involvement of nuclear factor κB in hormone-naive disease. We used immunohistochemistry to investigate expression of p65, androgen receptor, Ki-67, and phosphorylation status of p65 at serine 536, in 154 tumor samples taken from patients before hormone ablation or radical treatment. Nuclear p65 expression was significantly associated with disease-specific mortality: P = .005; hazard ratio, 2.2. When patients were stratified according to androgen receptor status, this relationship was abolished in low androgen receptor-expressing patients and potentiated in high androgen receptor-expressing patients: P = .002; hazard ratio, 3.1. Ki-67 expression was also prognostic of shorter disease-specific mortality: P = .001; hazard ratio, 2.3. When the cohort was stratified according to androgen receptor status, this relationship held for high androgen receptor expressers but not low expressers: P = .0003; hazard ratio, 3.5. Neither androgen receptor nor p65 phosphorylated at S536 were significantly prognostic when considered individually. These data suggest that future prostate cancer treatments that target nuclear factor κB signaling should be assigned primarily to patients with concomitant high nuclear p65 and androgen receptor expression.