Pleiotropic functional properties of androgen receptor mutants in prostate cancer

Abstract

The androgen receptor (AR) signaling pathway plays an important role during the development of the normal prostate gland, but also during the progression of prostate cancer on androgen ablation therapy. Mutations in the AR gene emerge to keep active the AR signaling pathway and to support prostate cancer cells growth and survival despite the low levels of circulating androgens. Indeed, mutations affecting the ligand binding domain (LBD) of the AR have been shown to generate so-called "promiscuous" receptors that present widened ligand specificity and allow the stimulation of these receptors by a larger spectrum of endogenous hormones. Another class of mutations, arising in the amino-terminal domain (NTD) of the receptor, modulate AR interactions with coregulators involved in cell proliferation regulation. Besides characteristics of these well-known types of mutations, the properties of other classes of AR mutants recently described in prostate cancer are currently under investigation. Most interestingly, in addition to their potential role in the mechanisms which allow prostate cancer cells to escape androgen ablation therapy, data suggest that certain AR mutations are present early in the natural history of the disease and may play a role in many aspects of prostate cancer progression. Surprisingly, singular truncated AR devoid of their carboxy-terminal end (CTE) region seem to exert specific paracrine effects and to induce a clonal cooperation with neighboring prostate cancer cells, which may facilitate both the invasion and metastasis processes. In this article, we review the functional properties of different classes of AR mutants and their potential impact on the natural history of prostate cancer. Hum Mutat 0, 1-14, 2008. (c) 2008 Wiley-Liss, Inc.

Androgen Receptor Controls EGFR and ERBB2 Gene Expression at Different Levels in Prostate Cancer Cell Lines

“…These authors identified low levels of expression of ARDCTD in AAR PCa xenografts. Interestingly, different point mutations introducing premature stop codons were identified in mRNA extracted from 16% of AAR PCa metastasis (29,(44)(45)(46).…”

ETS family transcription factors collaborate with alternative signaling pathways to induce carcinoma from adult murine prostate cells

“…It has been proposed that in addition to an autocrine mechanism (37), AR signaling in PCa cells can act on neighboring malignant cells in a paracrine manner (38). To test whether the observed synergy between ERG and AR occurs in a cellautonomous manner, we compared the effect of mixing prostate cells infected separately or coinfected with ERG and AR lentiviruses (Fig.…”

Characterization of Androgen Receptor Structure and Nucleocytoplasmic Shuttling of the Rice Field Eel

“…Mutation analysis confirmed that the LBD is essential for DHT-induced nuclear import of eAR and following transactivation function in the nucleus. The LBD mutations were indeed observed in human complete androgen insensitivity syndrome and partial androgen insensitivity syndrome diseases and in prostate cancer (1,2). Evolutionarily, three ␣-helices (eH3, eH4, and eH5) in the LBD are spatially essential for the AR function despite the different amino acid sequence; therefore, the structure of three ␣-helices has been conserved from eels to humans during vertebrate evolution.…”

“…3 The activated AR is translocated into the nucleus for a cascade of androgen signaling. AR mutations are frequent in metastatic prostate cancer, and more than 70 single-base substitutions have been described so far in prostate cancer (1,2), which would be one of the main causes of androgen-independent prostate cancer. Although great progress has been made, development of prostate cancer is a complicated process, and its molecular mechanism remains elusive.…”