AR is a steroid hormone receptor that acts as a ligand-dependent transcription factor. Once the ligand binds, AR translocates to the nucleus of the cell where dimerized receptors bind to enhancer and promoter regions termed androgen response elements (AREs) of target genes. This leads to the initiation of transcription, cell proliferation and survival, and negative feedback to inactivate AR transcription. Ligands that bind to AR principally include testosterone (T) and 5a-dihydrotestosterone (DHT). Other androgens such as androstenedione, androstenediol, and dehydroepiandrosterone (DHEA) have also been shown to bind AR, albeit with much less potency than T and DHT. The levels of circulating androgens differ significantly between males and females. T and DHT are present at the highest concentrations in males while in females they are at the lowest compared to other androgens. Given the differences in potency, the majority of AR activation in females will be likely due to T and DHT. AR also has the potential to be activated through ligand-independent mechanisms, including through interactions with PI3K/AKT, ERK, mTOR, and Wnt/β-catenin signalling pathways (reviewed in Anestis et al.). AR activity is well established as a dependency of prostate cancer (PCa) throughout all stages of growth and progression, leading to the essential role of AR-directed therapies for PCa.
AR is expressed in various tissues in females as well, including breast tissue, and it is known to play a significant role in normal female biology, fertility, and breast development. AR is also commonly expressed in BC, and while sex steroid signalling is very well established as being critical to the development of BC at all stages, the role of AR signalling remains unclear. AR is broadly expressed across multiple types of BC, leading to its emergence as a target for BC therapeutics and the ongoing research exploring AR as a predictive and prognostic biomarker. AR is expressed in 30–80% of BC, with more common co-expression with ER+ (70–90%) over ER– cancer (20–30%).[13–15] The variation in expression across studies is due, in part, to differing definitions of AR positivity (Table 1). Recently, Ricciardelli et al. summarized the use of AR for BC prognosis and concluded that a higher median cut-off of AR positivity (≥ 78%) could more reliably predict BC survival compared to other commonly used cut-offs (1% or 10% nuclear positivity). Table 2 shows this variability in the definition of AR positivity across clinical trials, with a range of positive IHC staining from > 0% to 50%. The clinical significance of AR expression seems to differ based on the type of BC, which becomes more evident as we assess the prognostic value of AR by subtypes of BC.
Breast Cancer Res. 2022;24(79) © 2022 BioMed Central, Ltd.
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