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.

Androgen Receptor Survival Signaling Is Blocked by Anti-β2-microglobulin Monoclonal Antibody via a MAPK/Lipogenic Pathway in Human Prostate Cancer Cells

“…These observations also suggest that AR function could be bypassed by other redundant cell signaling networks mediated by soluble factors such as insulin-like growth factor I, epidermal growth factor, keratinocyte growth factor, and interleukin-6 (19,20,50,51). Additional studies may be warranted to define how the triad relationship would function in normal versus cancer cells and in clinical prostate cancer, which characteristically contains cells with heterogeneous arrays of AR, including AR gene amplification and mutation and AR protein overexpression and silencing (52)(53)(54). In addition, the data presented in this communication are collected from the study of established AR-positive human prostate cancer cell lines, and further investigation of this concept in primary prostate cancer cells might be of importance.…”

Pro-survival and anti-apoptotic properties of androgen receptor signaling by oxidative stress promote treatment resistance in prostate cancer

“…Mutations in the AR gene may change its ligand binding characteristics or its transcriptional activity, resulting in the modulation of its target gene expression (Brooke et al 2008, Brooke & Bevan 2009). In addition to AR mutations, several AR splice variants that exhibit transcriptional activity even in the absence of androgen and contribute to the promotion of CRPC have recently been identified (Dehm et al 2008, Guo et al 2009, Hu et al 2009, Sun et al 2010, Watson et al 2010.…”

Repression of Androgen Receptor Activity by HEYL, a Third Member of the Hairy/Enhancer-of-split-related Family of Notch Effectors

“…Treatment for non-organ-confined prostate cancer usually involves administration of luteinizing hormone-releasing hormone analogs, which abrogate the production of testicular androgens, and/or antiandrogens, which bind to and block the activity of the AR. In the majority of cases, patients initially respond well to such treatment, but after a median of 2 years, tumors progress toward the more aggressive "androgen-independent" stage of the disease (3). The postulated molecular mechanisms that drive the transition to androgen independence include mutation and amplification of the receptor, altered levels/distribution of coregulator proteins, and growth factor-activated pathways (2)(3)(4).…”

“…In the majority of cases, patients initially respond well to such treatment, but after a median of 2 years, tumors progress toward the more aggressive "androgen-independent" stage of the disease (3). The postulated molecular mechanisms that drive the transition to androgen independence include mutation and amplification of the receptor, altered levels/distribution of coregulator proteins, and growth factor-activated pathways (2)(3)(4). At this stage of the disease, patients have a median survival of 12-18 months; thus, it is important to better understand the mechanisms that regulate AR activity and drive prostate cancer progression.…”