Racial Disparities in Expression of GDF15 and NFκB in Prostate Cancer and Benign Prostatic Epithelium

Abstract

Prostate cancer (PC) outcomes are more adverse for African-American (AA) than white (W) men. Growth differentiation factor 15 (GDF15, PDF, NAG-1) is a stress-induced anti-inflammatory cytokine with immunosuppressive and tumor growth-promoting functions. GDF15 inversely regulates NFκB, a transcription factor enabling pro-inflammatory gene expression and becomes constitutively activated in androgen-independent PC. Tissue microarrays (TMAs), prepared from prostatectomy tissue at three institutions, comprised 688 cases (364 W and 324 AA). Each case included ≥3 tumor punches plus ≥3 non-neoplastic punches. TMAs were stained separately for GDF15 and NFκB and evaluated by two pathologists, using the 0-3+ scale. PC, compared to benign epithelium, had elevated mean GDF15 expression (1.93 vs. 0.99) and also, NFκB (1.18 vs. 0.96, both P<0.0001). Only in AA men did PC show gradewise or stagewise altered expression of these markers. In AA men, GDF15 expression fell as stage rose in PC (P=0.007) and also in benign epithelium (P =0.003). In W men, GDF15 expression in benign epithelium fell as stage (P=0.01) and grade (P=0.01) rose. NFκB expression was higher in AA than W men only in high-grade PC (P =0.01). NFκB expression rose with increasing tumor grade only in AA men (P =0.027) and in the benign prostate component only in W men (P=0.007). Benign and tumor NFκB expression did not vary with stage. PC showed significant alterations in GDF15 and NFκB expression in accord with cancer aggressiveness in AA men only: stagewise decrease in GDF15, and gradewide increase in NFκB.  Findings suggest a disparity for immune response by race in prostate carcinogenesis.