Estrogen Receptors in Epithelial-Mesenchymal Transition of Prostate Cancer

Abstract

Prostate cancer (PC) remains a widespread malignancy in men. Since the androgen/androgen receptor (AR) axis is associated with the pathogenesis of prostate cancer, suppression of AR-dependent signaling by androgen deprivation therapy (ADT) still represents the primary intervention for this disease. Despite the initial response, prostate cancer frequently develops resistance to ADT and progresses. As such, the disease becomes metastatic and few therapeutic options are available at this stage. Although the majority of studies are focused on the role of AR signaling, compelling evidence has shown that estrogens and their receptors control prostate cancer initiation and progression through a still debated mechanism. Epithelial versus mesenchymal transition (EMT) is involved in metastatic spread as well as drug-resistance of human cancers, and many studies on the role of this process in prostate cancer progression have been reported. We discuss here the findings on the role of estrogen/estrogen receptor (ER) axis in epithelial versus mesenchymal transition of prostate cancer cells. The pending questions concerning this issue are presented, together with the impact of the available data in clinical management of prostate cancer patients.

Keywords: Estrogens; epithelial mesenchymal transition (EMT); estrogen receptors (ERs); metastasis; prostate cancer (PC).

Figure 1

Pathways controlling the epithelial-mesenchymal transition (EMT) program in prostate cancer (PC). Growth factors (e.g., transforming growth factor β (TGF-β), fibroblast growth factor (FGF), hepatocyte-derived growth factor (HGF), epidermal growth factor (EGF) and insulin-like growth factor 1 (IGF-1) released by the tumor microenvironment activate their cognate receptors (GFR, growth factor receptors; TGFβ-R, TGFβ receptor) thereby triggering downstream pathways. Through phosphoinositide-3 kinase (PI3-K), mitogen activated protein kinase (MAPK), small mother against decapentaplegic (Smad), glycogen synthase kinase-3 β (GSK3β), and nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), growth factors increase the activity of transcriptional repressors of Zinc finger E-box-binding homeobox 2 (ZEB2), Twist, and Snail families. They, in turn, down-regulate E-cadherin and other epithelial cell markers, while inducing mesenchymal proteins [9,10,11,12,13,14,25,26,35]. As the ligand-bound steroid receptors (SRs) trigger rapid activation of these signaling circuits [27,28,29], it might be hypothesized that such activation also contributes to EMT in PC. Canonical wingless-INT (Wnt) is implied in EMT of PC through activation of GSK3β. Stabilization and nuclear translocation of β-catenin then follow. This latter event leads to phosphorylation and nuclear translocation of snail family transcriptional repressors 1 (SNAI1). In such a way, the transcriptional activity of SNAI1 is enhanced [35]. Neurogenic locus notch homolog protein (Notch) 1–4 trans-membrane receptors can be activated by membrane-tethered ligands in mammals. Proteolytic cleavage of Notch receptors then follows, with the subsequent release of the Notch intracellular domain (NICD), which then enter nuclei to activate the transcription factors hairy and enhancer of split (HES) 1 and 2 as well as HES 1 related (HEY1). Through NF-kB, they control the expression of genes involved in EMT, such as Snail [13]. Mutually reinforcing mechanisms promoting the EMT program also occur. HES 1 and 2 as well as HEY1, indeed, positively affect HER2 (Erb-B2) transcription, thereby creating an activator loop of Erb-B2-dependent signaling. In such a way, PI3-K- and MAPK-dependent signaling is amplified. A role for the Notch pathway in EMT and spreading of PC has been reported [36].

Figure 2

Estrogen receptor (ER) α or β control the epithelial mesenchymal transition (EMT) program in prostate cancer (PC). Left panel: the ligand activated ERα might induce EMT through transcriptional up-regulation of Neurogenic locus notch homolog protein 1 (NOTCH1) [71] or nuclear enriched abundant transcript 1 (NEAT-1) [70]. Phosphoinositide 3-kinase (PI3-K)/AKT and Ras/Mitogen activated protein kinase (MAPK) pathways both induce EMT of PC [25,26]. As the ligand-bound ERα triggers activation of both these pathways in target cells [27,28,29], it might be argued that such activation leads to EMT in PC. Right panel: the ligand activated ERβ1 hinders EMT by repressing the transcription of hypoxia-induced factor 1α (HIF-1α) and promoting its degradation by proteasome [93]. By stabilizing HIF-1α, ERβ2 and 5 promote EMT [46]. Under certain conditions, ERβ1 could dimerize with androgen receptor (AR) upon being challenged with estrogens. Sex determining region Y box 4 (SOX4) up-regulation follows and this event leads to EMT in PC [102].