Interplay between genomic alterations and androgen receptor signaling during prostate cancer development and progression

Abstract

Advanced prostate cancer (PCa) treated with androgen deprivation therapy (ADT) eventually relapses to an ADT-resistant disease referred to as castration-resistant PCa (CRPC). Recent integrative analyses of PCa genomes have led to the elucidation of potential subtypes that are revelatory to the development of PCa as well as the mechanisms of resistance to ADT and CRPC progression. These studies have confirmed that alterations in the androgen receptor (AR) signaling axis are central to CRPC progression, and have uncovered complex mechanisms by which AR and other components of the AR signaling axis affect, and are affected by, genomic changes and epigenetic transformations. Among the most frequent alterations in CRPC are direct alterations in the AR gene. These AR gene alterations include AR amplification, point mutations, and more recently AR gene rearrangements leading to expression of truncated, constitutively active AR splice variants that are impervious to ADT. In this review, we will highlight genomic alterations that are important for development and progression of PCa, with a focus on how these alterations affect, and are affected by, activity of the AR signaling axis.

Fig. 1

A schematic of the AR gene structure is shown with cryptic exons (not to scale). Genomic regions involved in AR gene rearrangements associated with enhanced expression of truncated AR variants are indicated with dashed lines (above). The domain structure of full-length AR and truncated AR variants with included exons are indicated (below). Regular AR exons are in gray, cryptic exons in white. NH₂-terminal domain (NTD), DNA-binding domain (DBD), ligand binding domain (LBD)

Fig. 2

The relationship between PCa developmental subtypes is depicted on top. The relationship between developmental subtypes and treatment subtypes is largely unknown but subsequent changes to AR in response to ADT can be organized into the hierarchical categories depicted on the bottom