Nuclear Estrogen Receptors in Prostate Cancer: From Genes to Function

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.

Keywords: alternative splicing; cancer transcript variants; estrogen receptors; estrogen-receptor-targeting drugs; estrogens; gene regulation; prostate cancer.

Figure 1

Representation of ERα and ERβ sex-specific tissue distribution. The picture is not indicative of absolute receptor expression levels.

Figure 2

Schematic structures of estrogen receptors’ (ERs) isoforms. Different functional domains are highlighted: the N-terminal transactivation domain NTD/AF-1 (A/B), the DNA-binding domain (C), a hinge region (D), and the C-terminal cofactor interaction domain AF-2 and a ligand-binding domain (LBD) (E/F).

Figure 3

ERs can act through genomic and non-genomic pathways in PCa. In the genomic pathway, estrogen triggers the dimerization of ERs and their nuclear translocation to regulate the transcriptional activity of genes. ERs can directly control the transcription of genes bearing the estrogen response element (ERE) in their promoter region. In addition, ERs can modulate gene transcription through protein−protein interactions with other transcription factors (TF), which can mediate the recruitment of ERs at promoters without EREs. In the non-genomic pathway, membrane-associated ERs can participate in signal transduction and modulate the activation of key enzymes and molecular pathways, thus resulting in the indirect regulation of transcriptional programs. Known ER-regulated transcriptional programs in PCa: (I) ERα: transactivation of proliferative, apoptotic, survival, differentiation, vasodilation, autophagy, and inflammation targets; transactivation of oncogenes and non-coding RNAs. (II) ERβ1 transactivation of apoptotic, anti-proliferative, anti-invasive, and anti-inflammatory targets; repression of AR, oncogenes, and hypoxic genes. (III) ERβ2 and ERβ5—stabilization of the HIF-1α protein and induction of hypoxic genes. Created with BioRender.com, accessed on 10 July 2023.

Figure 4

Anti-estrogen molecules’ mode of action. Androgens are the substrate for estrogen production, mediated by the aromatase (CYP19A1) enzyme. Estrogens bind and activate ERs, thus regulating target genes’ transcription. The synthesis of estrogens may be blocked by specific inhibitors. SERDs are ER antagonists that bind the receptor, block its migration to the nucleus, and inhibit receptor-ERE interaction. SERD-ER complexes are degraded by the proteosome. PROTACs are bispecific ligands binding both ER and the E3 ubiquitin ligase, which, in turn, mediates the ubiquitination of the complex, leading to its degradation. SERM competitively binds ERs. The SERM-ER complex can interact with ERE sequences and co-repressors, inhibiting the transcription of target genes. However, this effect is tissue-specific and co-activators may be recruited in certain tissues, such as the endometrium and bone. CERANs exert antagonistic action by blocking AF1 and AF2 transcriptional activation domains via co-repressor recruitment. SERCAs covalently bind to an ER cysteine residue (C530), inhibiting the receptor activation and gene transcription. Selective ERβ agonists may be used to upregulate anti-proliferative signals in prostate cancer cells.