On the origins of the androgen receptor low molecular weight species

Abstract

Prostate cancer (CaP), a commonly diagnosed malignancy, is readily treated by androgen ablation. This treatment temporarily halts the disease, but castration-resistant neoplasms that are refractory to current therapies emerge. While these neoplasms are no longer dependent on physiological levels of androgens, they remain reliant on the expression of the androgen receptor (AR). There are multiple mechanisms by which CaP cells circumvent androgen ablation therapies. These include AR mutations that broaden ligand specificity, AR overexpression, AR activation by growth factors and cytokines, overexpression of AR co-activators, altered steroid metabolism, and a locus-wide histone transcriptional activation of some AR targets. This review focuses on a more recently described mechanism: the expression of low molecular weight AR species that are missing the ligand-binding domain and function independently of ligand to drive proliferation. The etiology, biological activity, unique features, predictive value, and therapeutic implication of these androgen receptor isoforms are discussed in depth.

Fig. 1

Schematic representation of the AR gene and AR splice variants. a The human AR gene is encoded by eight exons that are separated by large intronic regions. Exon 1 encodes the N-terminal transactivation domain (blue), exons 2 and 3 encode the two zinc fingers of the DNA-binding domain (red), exon 4 encodes the hinge region (green) and exons 5, 6, 7, and 8 encode the ligand-binding domain (yellow). b The various types of splice variants contain specific exons as well are novel sequences encoded by intronic regions. Novel sequences derived from intronic sequences are denoted in black