Androgen receptor

As a member of the steroid receptor family, the androgen receptor (AR) belongs to the superfamily of nuclear transcription factors(nuclear receptors). The androgen receptor family consists of a group of structurally related nuclear receptors that regulate the action of steroid hormones (Narayanan R et al. 2018). The family of steroid receptors also includes others such as glucocorticoid receptors, mineral corticoid receptors, estrogen and progesterone receptors (Claessens F et al. 2017). AR regulates multiple cell effects such as proliferation, apoptosis, migration, invasion, and differentiation (Culig Z et al (2014).

The specific (natural) ligands of the androgen receptor are the sex hormones testosterone and dihydrotestosterone. In humans, the androgen receptor is encoded by the AR gene, which is located on Xq11-12, i.e. on the long arm of the X chromosome. In humans, the AR is produced in most tissue types. The different activities are due to a number of proteins that act as coactivators or core compressors of the receptor.

The androgen receptor (AR) has a direct influence on the transcription of certain genes. AR is (like the ER = estrogen receptor) bound to the heat shock protein 90, which maintains the binding affinity of the receptor. The binding of the AR to its ligands testosterone or dihydrotestosterone triggers a conformational change of the receptor. The heat shock protein is cleaved off. The receptor dimer is transferred from the cytosol to the cell nucleus. Here, the complex binds to so-called androgen receptor response elements (HRE) of the DNA, depending on core compressors or coactivators. The mRNA formed from the initiated transcription is transported to the ribosomes, where it is transcribed into specific proteins. In humans, the androgen receptor thus determines the male appearance throughout the entire life.

Mutations in the AR gene can, depending on their localisation, induce disorders at all levels of the androgen receptor mechanism, e.g. disorders in androgen binding, DNA binding or transactivation. With over 90% of all mutations, point mutations represent the largest group of androgen receptor gene defects. This results in an amino acid exchange in the receptor gene; splice defects or non-sense mutations are less frequent.

Androgen insensitivity: For example, if there is a mutation in the androgen receptor of the male genotype (46, XY), this can lead to complete(CAIS) or partial androgen insensitivity(PAIS; OMIM 300068) (Mongan NP et al. 2015). The endocrinological parameters of these androgen receptor defects partly correspond to those of 5a-reductase deficiency. Due to the different phenotype, both the time of clinical manifestation and the "clinical picture" can vary significantly. Phenotypically male patients often only become conspicuous due to an inadequate puberty development or an unfulfilled desire for children in the case of infertility. Women with complete androgen resistance often only become conspicuous through primary amenorrhoea. In the case of androgen resistance, for example, the molecular biological detection of "somatic mosaics" provides a conclusive explanation for the sometimes pronounced genotype-phenotype discrepancies (Wang H et al. 2019).

Androgen receptors and breast carcinoma: AR expression depends on both the histopathological and molecular subtype; luminal carcinomas show the highest AR expression among the breast carcinoma subtypes. In estrogen receptor (ER)-positive carcinomas, AR co-expression has a clearly positive prognostic impact on overall (OS) as well as disease-free survival. In luminal (ER-positive and HER2-negative) carcinomas, AR activation has an antiproliferative effect. The AR acts as a tumour suppressor. However, in endocrine resistant tumours, AR can promote tumour growth.

The new generation of "androgen receptor-targeted therapeutics" for breast cancer (60-80% of breast cancers are characterized by AR-positivity) now plays an important role.

Androgen receptor blockers: Substances such as cyproterone acetate (6-chloro-1α,2α-methylene-17-acetoxy-pregna-4,6-dien-3,20-dione) and flutamide block androgen receptors, e.g. at the prostate, thus cancelling out the effect of androgens. Cyproterone acetate is used for moderate to severe acne, seborrhoea, alopecia androgenetica (see alopecia androgenetica in women, alopecia androgenetica in men) and hirsutism.

Androgen receptor anatagonists in prostate cancer (Culig Z et al 2014): Treatment with the androgen receptor inhibitor apalutamide can effectively delay the time without metastases and the time until symptoms worsen in patients with non-metastatic prostate cancer and high risk of metastasis compared to placebo (Smith MR et al 2018).

Nomenclature: The androgen receptor has the systematic name NR3C4 (NR=nuclear receptor, 3 subfamily3, C for group C, 4 for gene 4 - see below nuclear receptors).

SARMs: However, the discovery of selective androgen receptor modulators (SARMs) and other tissue-selective nuclear hormone receptor modulators that activate their related receptors in a tissue-selective manner, offers the possibility to greatly enhance the beneficial effects of androgens and other hormones in target tissues, reduces undesirable side effects (Narayanan R et al. 2018).

1. Claessens F et al (2017) Comparing the rules of engagement of androgen and glucocorticoid receptors. Cell Mol Life Sci 74:2217-2228.
2. Culig Z et al (2014) Androgen receptor signaling in prostate cancer. Cancer Metastasis Rev 33:413-427.
3. Kono M et al (2017) Androgen Receptor Function and Androgen Receptor-Targeted Therapies in Breast Cancer: A Review. JAMA Oncol 3:1266-1273.
4. Mongan NP et al (2015) Androgen insensitivity syndrome. Best Pract Res Clin Endocrinol Metab 29:569-580.
5. Narayanan R et al (2018) Development of selective androgen receptor modulators (SARMs). Mol Cell Endocrinol 465:134-142.
6. Smith MR et al (2018) Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. New England Journal of Medicine, online pre-publication DOI: 10.1056/NEJMoa1715546
7. Wang H et al (2019) Somatic mosaicism of androgen receptor gene in an androgen insensitivity syndrome patient conceived through assisted reproduction technique. Mol Genet Genomic Med: e906.