A new trick of an old molecule: androgen receptor splice variants taking the stage?!

Abstract

Prostate cancer is the second leading cause of cancer-related death in American men. Although most prostate cancers are initially androgen-dependent and respond to androgen ablation therapy, majority of them eventually relapse and progress into incurable castration-resistant (or hormone refractory) prostate cancer. The underlying mechanisms are the focus of intensive investigation for development of more effective treatment. Mounting evidence from both clinical and basic research has demonstrated that the activity of the androgen receptor (AR) is still required for castration-resistant prostate cancer. Multiple mechanisms by which AR is re-activated under androgen-depleted conditions may be involved in the development of castration resistance. The recent identification of AR splicing variants may add another layer of complexity in AR biology. The present review summarizes recent progress in study of AR splicing variants in prostate cancer.

Keywords: alternative splicing.; androgen receptor; prostate cancer; splicing variants.

Figure 1

Schematic structure of human AR splice variants reported in GenBank. The hatched cassettes stand for the cryptic exons. Solid thick lines represent the transcribed exon sequences. U: unique N- or C-terminal sequence.

Figure 2

Subcellular localization of AR3/AR-V7. COS-1 and DU145 cells were transfected with an AR3 expressing plasmid. At 48h post-transfection, cells were stained with an anti-AR N-terminal antibody (green) and nuclei were visualized with DAPI (blue). In DU145 cells, both nuclear and cytoplasmic staining is observed.

Figure 3

Immunohistochemistry analysis on human prostate tissue sections using the AR3 specific antibody (ref 12). Left, in benign tissues, AR3 is primarily detected in stromal and basal compartments whereas virtually no expression in luminal epithelial cells. Center, in adjacent prostatic intraepithelial neoplasia (PIN), AR3 is detectable in luminal epithelial cells. Right, in hormone-resistant (HR) tumors, nuclear staining of AR3 is enhanced.