Aberrant AR Signaling as a Function of Declining Androgen

摘要

This was an Exploration - Hypothesis Development Award (EHO) in which we modeled, in a mouse model system of xenograft human tumor growth, the natural androgen decline in the aging male (ADAM) as it occurs after the age of 40 years in humans. We explored the possibility that different testosterone levels may influence prostate tumor growth. We have completed the proposed study and found that all mice receiving testosterone at declining concentrations (even as little as 0.5 mg) developed xenograft tumors at about the same time and rate as fully androgenized mice. Only in androgen ablated mice did the tumors developed after months of delay. It therefore seems that tumor growth can be maintained at very low testosterone levels. We analyzed in detail PSA gene expression in tumors from the two extreme groups of animals (no testosterone and normal levels of testosterone) and found that tumors from ablated mice had on average higher steady-state levels of PSA mRNA than those in the testosterone group. However, tumors from ablated mice displayed elevated histone H3-K9/K14 acetylation across the entire body of the PSA gene. The data therefore indicates that loci-specific chromatin alterations contribute to basal gene expression of specific AR target genes in androgen-independent PCa cells and may thus contribute to the androgen-independent phenotype of these cells.