Androgen receptors beyond prostate cancer: an old marker as a new target

Abstract

Androgen receptors (ARs) play a critical role in the development of prostate cancer. Targeting ARs results in important salutary effects in this malignancy. Despite mounting evidence that ARs also participate in the pathogenesis and/or progression of diverse tumors, exploring the impact of hormonal manipulation of these receptors has not been widely pursued beyond prostate cancer. This review describes patterns of AR expression in a spectrum of cancers, and the potential to exploit this knowledge in the clinical therapeutic setting.

Conflict of interest statement

Conflicts of Interest

The authors have no conflicts of interests to disclose.

Figures

Figure 1. The road to (androgen) independence

AR-negative prostate adult stem cells generate AR-negative transit amplifying cells, AR-negative intermediate cells and AR-positive luminal secretory cells. Once therapeutic circulating androgen blockade ensues, AR-positive luminal cells die, giving origin to the adaptive (selected AR-positive luminal cells will continue to thrive despite lack of androgen exposure) and clonal theory of resistance (pre-existent AR-negative cells develop into a malignant clone). Castration-resistant prostate cancer might develop via ligand-dependent (tissue steroidogenesis, AR mutations, AR amplification) and ligand-independent pathways (heightened AR nuclear translocation, AR cross-talk with additional pathways, disturbing the balance between co-activators and co-repressors).

Figure 2. The fate of testosterone in prostatic tissues

Testosterone circulates in the blood and is bound to albumin, whereas free testosterone is introduced into prostate cells and is subsequently converted to DHT by 5-alpha-reductase. Binding of DHT to the AR induces dissociation from HSPs and receptor phosphorylation. The AR dimerizes and can bind to androgen-response elements in the promoter regions of target genes, leading to growth, survival and production of PSA. Enzalutamide, formerly called MDV3100, exerts its mechanism of action during several steps in the AR signaling pathway including inhibition of AR binding to androgens, inhibition of nuclear translocation of AR, inhibition of AR association to DNA, and AR amplification. As some of those aberrations may occur late in the disease, it is unknown at this point if enzalutamide will have a role upfront in the management of prostate cancer. Abbreviations: AR, androgen receptor; DHT, dihydrotestosterone; GTA, general transcription activation; HSP, heat-shock protein; SHBG, sex-hormone-binding globulin; AKT, akt serine/threonine kinase; DHEA, dihydroepiandrosterone; ERK, extracellular signal-regulated kinase; P, phosphorylated residues; PI3K, phosphoinositide 3-kinase; PTEN, phoshatase and tensin homolog.

Figure 3. Androgen blockade plus mTOR inhibitors: A prime candidate for combination hormonal treatment

The mTORC2/AKT/AR pathway (red arrows) leads to tumor cell proliferation. Rapamycin combined with bicalutamide has an apoptosis-inducing effect in prostate cancer. Rapamycin inhibits both mTOR complexes, mTORC1 with raptor and mTORC2 with rictor; nevertheless abrogation of mTORC2, a kinase for AKT phosphorylation, further inhibits the AR transcription cascade in an AKT-dependent manner. As a counterpoint, abrogation of mTORC1 produces AKT/AR-independent apoptosis, though it continues to stimulate the AR transcriptional cascade and AKT phosphorylation. According to the suggested cross-talk, it would take a combination of androgen blockade plus mTOR inhibitors to fully abrogate the mTORC2/AKT/AR pathway. Barnett et al. [44] found that, out of 47 tumors evaluable by immunohistochemistry, 36% had PTEN loss which was associated with an increased relapse in high risk prostate cancer treated with chemotherapy followed by surgery. PTEN loss activates the AKT/mTOR pathway [45] thus supporting the use of mTOR inhibitors in this condition. Abbreviations: AR, androgen receptor; AKT, aKT serine/threonine kinase.