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Review
. 2023 Aug 7;11(8):2215.
doi: 10.3390/biomedicines11082215.

Beyond Prostate Cancer: An Androgen Receptor Splice Variant Expression in Multiple Malignancies, Non-Cancer Pathologies, and Development

Kimberley D Katleba  1   2 , Paramita M Ghosh  1   3   4 , Maria Mudryj  1   2
Affiliations
Review

Beyond Prostate Cancer: An Androgen Receptor Splice Variant Expression in Multiple Malignancies, Non-Cancer Pathologies, and Development

Kimberley D Katleba et al. Biomedicines. .

Abstract

Multiple studies have demonstrated the importance of androgen receptor (AR) splice variants (SVs) in the progression of prostate cancer to the castration-resistant phenotype and their utility as a diagnostic. However, studies on AR expression in non-prostatic malignancies uncovered that AR-SVs are expressed in glioblastoma, breast, salivary, bladder, kidney, and liver cancers, where they have diverse roles in tumorigenesis. AR-SVs also have roles in non-cancer pathologies. In granulosa cells from women with polycystic ovarian syndrome, unique AR-SVs lead to an increase in androgen production. In patients with nonobstructive azoospermia, testicular Sertoli cells exhibit differential expression of AR-SVs, which is associated with impaired spermatogenesis. Moreover, AR-SVs have been identified in normal cells, including blood mononuclear cells, neuronal lipid rafts, and the placenta. The detection and characterization of AR-SVs in mammalian and non-mammalian species argue that AR-SV expression is evolutionarily conserved and that AR-SV-dependent signaling is a fundamental regulatory feature in multiple cellular contexts. These discoveries argue that alternative splicing of the AR transcript is a commonly used mechanism that leads to an expansion in the repertoire of signaling molecules needed in certain tissues. Various malignancies appropriate this mechanism of alternative AR splicing to acquire a proliferative and survival advantage.

Keywords: androgen receptor; development; malignancies; pathologies; splice variants.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic of the cryo-EM-derived three-dimensional structure of ligand bound AR binding to AREs, interacting with co-regulators p300 and SRC-3. Note that in the dimerized molecule, the NTDs have slightly different confirmations and that the hinge region is hidden. The NTDs interact with each other and wrap around the LBD.
Figure 2
Figure 2
Schematic of homo and hetero dimers of FL-AR and AR-SV. The structures of the AR-SV homodimer and FL-AR and AR-SV heterodimers are unknown; therefore, they are solely the authors’ representation to denote differences. Since the DBD (green) is retained in FL-AR and AR-SV isoforms, the molecules are tethered to DNA sequences. The absence of the LBD (orange) would alter the intermolecular and intramolecular interactions of the NTD (blue); hence, the structure of the dimer would be different, as would the assembly of AR interactors (represented by the light-colored clouds). The unique complement of AR interactors would regulate AR DNA binding, transcriptional activity, and subsequent distinct transcriptional output.
Figure 3
Figure 3
Schematic of the gene encoding AR, noting canonical and cryptic exons that give rise to the FL-AR and a subset of AR-SVs. The exons coding for the different domains are colored NTD-blue, alternative NTD-red, DBD-orange, hinge-yellow, and LBD-green. The cryptic intronic sequences found in AR-SVs are in shades of purple or black.
Figure 4
Figure 4
Male-to-female ratio of cancer incidence of the most common cancers (2023) [70].
See this image and copyright information in PMC

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