ANDROGEN SIGNAL-TRANSDUCTION AND PROSTATIC-CARCINOMA

In the prostate, androgen action affects the growth Of the gland, its morphology, and regulation of protein expression. Endocrine therapy of non-organ-confined tumors is based on the androgen dependence of the vast majority of prostatic carcinomas. Although initial response rates are high, this therapy is only temporarily effective. Critical molecular changes ultimately resulting in androgen independence of tumor cells are unknown at this time. The androgen signal-transduction cascade and its central element, the androgen receptor (AR), are possible targets for such changes. Immunohistological analysis using anti-AR antibodies has revealed the presence of AR in a vast majority of therapy-responsive as well as therapy-unresponsive prostatic carcinomas, indicating that loss of AR expression is not the reason for androgen independence. On the other hand, molecular-biology studies have revealed qualitative and quantitative impairment of AR expression in prostatic tumor cell lines that represent very late stages of prostatic carcinoma development. Mutant ARs were detected in the prostatic tumor cell line LNCaP and in two specimens from primary prostatic tumors. The LNCaP mutant AR as well as mutant AR715met, one of the mutant receptors detected in tumor tissue, show a gain of function as compared with the wild-type receptor. In addition to androgens, the natural activators of the AR, the LNCaP receptor is activated also by progestagenic and estrogenic steroids and by the nonsteroidal antiandrogen flutamide. AR715met is activated by adrenal androgens and progesterone in addition to androgens. Although determination of the frequency of point mutations in late prostatic carcinoma requires further investigation, these data imply that tumor progression in an androgen-ablated environment may be accompanied by aberrant AR activation.