Abstract
A promotional role for androgen receptor (AR) signaling in hepatocellular carcinogenesis is emerging. In pre-clinical models, including diethylnitrosamine- (DEN-) induced hepatocellular carcinoma (HCC), anti-androgen therapies delay hepatocarcinogenesis. However, pharmacologic anti-androgen therapy in advanced HCC patients fails, suggesting that AR plays a role in HCC onset. This study aims to characterize AR expression and function throughout DEN-induced liver inflammation and carcinogenesis and evaluate the efficacy of prophylactic AR antagonism to prevent hepatocarcinogenesis. We demonstrate that pharmacologic AR antagonism with enzalutamide inhibits hepatocellular carcinogenesis. With enzalutamide treatment, we observe decreased CYP2E1 expression, reducing DEN-induced hepatocyte death and DNA ethyl-adducts. AR protein expression analyses show that DEN causes an initial upregulation of AR in portal fibroblasts and leukocytes, but not hepatocytes, suggesting that hepatocyte-autonomous AR signaling is not essential for DEN-induced carcinogenesis. Ablating androgen signaling by surgical castration reduced pre-carcinogen Kupffer cell populations but did not alter DEN-mediated immune cell recruitment nor AR expression. In this study, we identified that anti-androgen interventions modulate mutagenic DNA adducts, tumour initiation, and immune cell composition. Additionally, we find that AR expression in hepatocytes is not present during nor required for early DEN-mediated carcinogenesis.
Highlights
The androgen receptor (AR) is an enticing therapeutic target in hepatocellular carcinoma (HCC)
To ensure steady-state concentrations of drug were achieved, doses were administered for two weeks prior to carcinogenic challenge consisting of two-thirds partial hepatectomy (PH) and IP injections of 50 mg/kg DEN at 24 h prior to and following the PH procedure
Vehicle-treated SHAM animals receiving DEN/PH alone served as untreated controls while animals orchiectomized (ORX) three weeks prior to carcinogen challenge served as anti-androgen phenotype positive controls
Summary
The androgen receptor (AR) is an enticing therapeutic target in hepatocellular carcinoma (HCC). The success of anti-androgen therapies in pre-clinical carcinogenesis models has yet to translate into humans as pharmacologic targeting of the AR-signaling axis consistently fails when studied in latestage HCC16,17. These findings support a hypothesis that inhibition of the liver carcinogenesis cascade may require early and prolonged intervention of the AR-signaling axis. In both carcinogen- and viral transgene-induced models, surgical castration as a therapeutic intervention demonstrates a precipitous decline in anti-carcinogenic activity with delayed o rchiectomy[3,4]. To test this hypothesis—and to interrogate mechanisms of action potentially explaining the efficacy of early antagonism of the AR signaling axis in HCC—we treated (i.e. before carcinogenic challenge) adult rats with enzalutamide (ENZ), a potent AR antagonist, in a diethylnitrosamine (DEN)-induced model of hepatocellular carcinogenesis
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