Mutations of the Androgen Receptor in PCA

In contrast to AR mutations detected in patients with androgen insensitivity syndromes, several structural changes of the AR in PCA lead to gain of function. This was first observed in LNCaP cells, whose mutant AR is efficiently activated by adrenal androgens, anti-androgens, and estrogenic or progestagenic steroids (17). In LNCaP cells, threonine at position 877 is mutated to alanine. The mutation changes the stereochemistry of the binding pocket of the AR. The first two mutations discovered in PCA patients have very similar functional consequences; in each of these two ARs, amino acid valine (at positions 715 and 730, respectively) is substituted by methionine (18,19). These ARs are increasingly activated by adrenal androgens, products of dihydrotestosterone (DHT) metabolism, and hydroxyflutamide. Higher AR activity was induced by these hormones, although there were no major changes in AR binding affinity. A more efficient AR activation by adrenal androgens and DHT metabolism may influence natural course of the disease. Hydroxyflutamide is a mixed antagonist/agonist whose agonistic properties may be enhanced in presence of mutated AR (20). There is evidence that anti-androgen treatment results with appearance of specific mutations in the AR. Some patients who failed endocrine treatment with hydroxyflutamide were subjected to a second-line treatment with bicalutamide and showed a time-limited response (21). Missense mutations of the AR were also discovered in patients who were treated with bicalutamide (22). Thus, knowledge on AR structure in PCA patients may be relevant to determine an appropriate endocrine treatment. More recent studies on AR structure revealed that, in some patients, AR point mutations that lead to loss of function or have no functional consequences also occur.

In general, the frequency of AR point mutations increases in late stages PCA (23). Most mutations detected in PCA are somatic, in contrast to inherited mutations associated with syndromes of androgen insensitivity. Mutant ARs were detected in bone specimens from patients who failed endocrine therapy (24). However, bone metastases are only infrequently used for AR studies because of ethical concerns.

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