Nuclear Estrogen Receptors in Prostate Cancer: From Genes to Function

SIMPLE SUMMARY: Estrogens are steroid hormones that interact with nuclear receptors (ERα and ERβ) and a membrane G-protein-coupled receptor (GPER) to regulate multiple physiological processes. Abnormal ERs and GPER signaling can lead to different disorders, including cancer, making them attractive drug targets. Estrogen-related pathways are implicated not only in breast cancer but also in prostate cancer, providing potential treatment opportunities. New compounds targeting ERs have led to therapeutic advancements, but cancer drug resistance remains a challenge. Genetic and biological mechanisms regulating the expression and activity of nuclear estrogen receptors in prostate cancer are discussed in this review. A comprehensive characterization of specific splice variants in prostate cancer subtypes might lead to new stratification and therapeutic opportunities. ABSTRACT: Estrogens are almost ubiquitous steroid hormones that are essential for development, metabolism, and reproduction. They exert both genomic and non-genomic action through two nuclear receptors (ERα and ERβ), which are transcription factors with disregulated functions and/or expression in pathological processes. In the 1990s, the discovery of an additional membrane estrogen G-protein-coupled receptor augmented the complexity of this picture. Increasing evidence elucidating the specific molecular mechanisms of action and opposing effects of ERα and Erβ was reported in the context of prostate cancer treatment, where these issues are increasingly investigated. Although new approaches improved the efficacy of clinical therapies thanks to the development of new molecules targeting specifically estrogen receptors and used in combination with immunotherapy, more efforts are needed to overcome the main drawbacks, and resistance events will be a challenge in the coming years. This review summarizes the state-of-the-art on ERα and ERβ mechanisms of action in prostate cancer and promising future therapies.