Prostate homeostasis and function are regulated by complex interactions between the fibromuscular stroma and secretory epithelium via locally-derived and systemic paracrine- and autocrine-acting growth factors and sex steroid hormones. Stromal tissue remodelling due to alterations in transforming growth factor beta (TGF-β) and sex steroid hormone signalling are associated with benign prostatic hyperplasia (BPH) and prostate cancer (PCa), two of the most common proliferative disorders affecting elderly men.
We previously demonstrated that GAGEC1, a member of cancer-testis associated antigens, is up-regulated in response to TGF-β in in vitro models of age-associated prostatic stromal remodelling. GAGEC1 expression is restricted to male and female reproductive tissues and is up-regulated in the prostates of patients with symptomatic BPH and PCa. Consistent with its restricted expression profile to classical steroidogenic tissues, GAGEC1 is induced by sex steroid hormones, particularly oestradiol and dihydrotestosterone. Transiently expressed recombinant GAGEC1 undergoes constant shuttling between cytoplasmic and nuclear cell compartments, a process that may be regulated via post-translational phosphorylation.
Our data suggest that age/disease-associated changes in TGF-β1 and sex steroid hormones may account for the reported increase in GAGEC1 expression in BPH and PCa. Functional analyses indicate that the biological activity of GAGEC1 is regulated via phosphorylation-dependent nucleo-cytoplasmic trafficking raising the possibility that GAGEC1 is involved in signal transduction mechanisms. Given that its expression is restricted in males to the prostate and testis, GAGEC1 represents a promising target for therapeutic intervention of BPH and PCa.