Low Tristetraprolin Expression is Associated with Lethal Prostate Cancer.

PURPOSE: Inflammation is linked to prostate cancer (PrCa) progression and is mediated by Nuclear Factor Kappa B (NFκB). Tristetraprolin is a key node of NFκB activation and we investigated its biological and prognostic role in lethal PrCa.

METHODS: In vitro assays assessed the function of tristetraprolin and the association between low mRNA tristetraprolin levels and lethal PrCa (metastatic disease or death) was assessed across independent prostatectomy cohorts: (i) nested case-control studies from Health Professionals Follow-up Study and Physicians' Health Study, and (ii) prostatectomy samples from Cleveland Clinic, Mayo Clinic, Johns Hopkins and MSKCC. Tristetraprolin expression levels in prostatectomy samples from patients with localized disease and biopsies of metastatic castration resistant PrCa (mCRPC) were assessed in a Cornell University cohort.

RESULTS: In vitro tristetraprolin expression was inversely associated with NFκB-controlled genes, proliferation and enzalutamide sensitivity. Men with localized PrCa and lower quartile of tumor tristetraprolin expression had a significant, nearly 2-fold higher risk of lethal PrCa after adjusting for known clinical and histological prognostic features (age, RP Gleason score, T-stage). Tristetraprolin expression was also significantly lower in mCRPC compared with localized PrCa.

CONCLUSIONS: Lower levels of tristetraprolin in human PrCa prostatectomy tissue are associated with more aggressive PrCa and may serve as an actionable prognostic and predictive biomarker.

IMPACT: There is a clear need for improved biomarkers to identify patients with localized prostate cancer in need of treatment intensification, such as adjuvant testosterone suppression, or treatment de-intensification, such as active surveillance. Tristetraprolin levels may serve as informative biomarkers in localized PrCa.