Warner et al. review the history of the oestrogen receptor beta isoform (ERβ), discovered in 1996 by Jan-Åke Gustafsson’s team at Karolinska Institutet, Stockholm, Sweden. The discovery of ERβ helped to resolve a novel endocrine pathway in the prostate, by elucidating that the potent androgen dihydrotestosterone could be metabolised to the oestrogenic metabolite 5α-androstane-3β,17β-diol (3β-Adiol). 3β-Adiol was found to be an agonist of the novel ERβ and, in experimental models, could oppose androgen signalling, making it a potential target for prostate cancer treatment.

Initially, ERβ was thought of as a ‘vestigial receptor’ because it had no proliferative effects in the uterus, although knockout studies suggested it was required for fertility in females. Functional roles in the prostate and breast have only been confirmed as recently as 2020, following the complete removal of the receptor that had eluded previous methods for generating ERβ knockout mice.

A number of natural and synthetic ligands to ERβ have been identified and have been effective at improving pathologies in rodent models of neurodegenerative diseases. Translation of these studies has been hampered by differences in ERβ signalling in rodents and humans. This is primarily due to the presence of receptor splice variants in humans/primates that are absent in rodents. Thus, better understanding of ERβ signalling and the role of splice variants in humans is required before the full potential of this promising therapeutic target can be realised.

Read the full article in Journal of Molecular Endocrinology 68 R1–R9