Prostate epithelial AR inactivation in mice prevents experimental prostate cancer progression induced reduction in intraprostatic DHT (#67)
In men androgens, testosterone (T) and its more potent 5α-reduced metabolite dihydroT (DHT) acting via the androgen receptor (AR), are the main sex hormones in the circulation and necessary for the development of prostate cancer. Intracrine androgen signalling involving AR, which regulates 5α-reductases (enzymes converting T to DHT) are involved in the origins and progression of prostate cancer. In the present work, we investigated the effect of PTEN tumor suppressor inactivation-induced prostate pathology on intracrine androgens and how this is regulated by intraprostatic AR.
Prostate histopathology as well as serum and intraprostatic androgens (liquid chromatography tandem mass spectrometry) and prostate 5α reductase expression (real-time RT-PCR) were compared between wild-type (WT) mice and prostate epithelia specific PTEN (PTENKO) and combined PTEN and AR knockout (PTENARKO) mice (Cre/loxP system).
Prostate specific PTEN inactivation (PTENKO males) featured increased prostate weight and severe epithelial pathology. In PTENARKO males prostate epithelial pathology was still present but the weight increase was not observed when AR inactivation was superimposed on PTEN inactivation. Surprisingly, intraprostatic DHT content was significantly reduced in PTENKO compared to WT (2.2±0.5 vs 8.8±1.1ng/mg; n=≥5; p=0.026), whereas AR inactivation (in PTENARKO males) significantly increased the intraprostatic DHT (14.8±3.5ng/mg) compared to both WT (p=0.048) and PTENKO (P<0.001). Prostatic expression of 5α-reductase2 mRNA was significantly increased in PTENARKO compared to WT (2.8-fold; p=0.04) and PTENKO (11.7-fold; p=0.018), whereas 5α-reductase1 was very low in all prostates. Serum T and DHT and intraprostatic T were not significantly (p>0.05) different between genotypes.
In conclusion, we demonstrate that prostate epithelium-specific AR inactivation does not prevent PTEN inactivation-induced severe prostate epithelial hyperplasia. However, the results suggest that during progression of experimental cancer, prostate cells may be sensitized to low levels of the potent androgen DHT, a feature that is prevented by epithelial AR inactivation.