The role of androgen receptor mutations in prostate cancer progression

Abstract

Prostate tumour growth is almost always dependent upon the androgen receptor pathway and hence therapies aimed at blocking this signalling axis are useful tools in the management of this disease. Unfortunately such therapies invariably fail; and the tumour progresses to an "androgen-independent" stage. In such cases androgen receptor expression is almost always maintained and much evidence exists to suggest that it may still be driving growth. One mechanism by which the receptor is thought to remain active is mutation. This review summarises the present data on androgen receptor mutations in prostate cancer, and how such substitutions offer a growth advantage by affecting cofactor interactions or by reducing ligand specificity. Such alterations appear to have a subsequent effect upon gene expression suggesting that tumours may "behave" differently dependent upon the ligand promoting growth and if a mutation is present.

Fig. (1)

Frequency and location of androgen receptor mutations associated with prostate cancer. The location and frequency of different single base mutations are given, highlighting where these substitutions lie in relation to functional domains of the androgen receptor.

Fig. (2)

Hormone therapy failure caused by AR mutation. (1) The unliganded AR exists in the cytoplasm associated with a large heterocomplex that holds it in a ligand binding competent state. (2) Upon ligand binding the receptor dimerises, translocates to the nucleus where it binds DNA and promotes gene transcription via the recruitment of accessory proteins, such as coactivators. (3) Non organ-confined prostate cancer is usually treated by blocking the AR pathway. This is achieved by blocking the production of androgen (using LHRH analogues) and/or antiandrogens. (4) Antiandrogens bind to the AR but do not promote an active conformation and instead block receptor function, at least in part, by promoting the recruitment of corepressors to the regulatory regions of target genes. (5) This therapy selects for cells that have mechanisms by which the tumour can grow in the androgen depleted environment. One such mechanism is that of AR mutation and in some cases these mutants provide a growth advantage because they reduce the ligand specificity of the receptor. Hence other ligands, such as the antiandrogens being used in treatment, are now able to promote an active conformation, the recruitment of coactivators and subsequently gene expression.

Fig. (3)

Surface representation of the AR coactivator groove. Representation of the AR AF-2 surface highlighting the L-shaped cleft and key residues important in coactivator binding. +1, +4 and +5 refer to the regions in which the 1^st, 4^th and 5^th amino acids of LxxLL and FxxLF-like motifs lie following binding. Image created using RasMol V2.6 using co-ordinates from [30].