Abstract
Prostate cancer is the commonest, non-cutaneous cancer in men. At present, there is no cure for the advanced, castration-resistant form of the disease. Estrogen has been shown to be important in prostate carcinogenesis, with evidence resulting from epidemiological, cancer cell line, human tissue and animal studies. The prostate expresses both estrogen receptor alpha (ERA) and estrogen receptor beta (ERB). Most evidence suggests that ERA mediates the harmful effects of estrogen in the prostate, whereas ERB is tumour suppressive, but trials of ERB-selective agents have not translated into improved clinical outcomes. The role of ERB in the prostate remains unclear and there is increasing evidence that isoforms of ERB may be oncogenic. Detailed study of ERB and ERB isoforms in the prostate is required to establish their cell-specific roles, in order to determine if therapies can be directed towards ERB-dependent pathways. In this review, we summarise evidence on the role of ERB in prostate cancer and highlight areas for future research.
Introduction
Prostate cancer is the commonest, non-cutaneous cancer in men, affecting 214 per 1000 European men. It is the second commonest cause of cancer death, accounting for 15% of all male cancers in developed countries (Heidenreich et al. 2011, Mottet et al. 2011). Ever since the landmark research of Huggins and Hodges (Huggins 1943, Huggins & Hodges 1972) demonstrating the importance of steroid hormones in the development and treatment of prostate cancer, there has been interest in the effects of estrogen on the prostate gland. Initially, hormone treatment for prostate cancer involved manipulation of systemic hormone levels with exogenous estrogen therapy (in the form of high-dose diethylstilbestrol) to suppress androgen production indirectly via the hypothalamo–pituitary–gonadal axis (Huggins & Hodges 1972). However, the unacceptably high rates of cardiovascular side effects associated with systemic estrogen therapy, coupled with the advent of alternative treatment options, resulted in reduced use of this therapy (Morales & Pujari 1975). Consequently, for a period of time, interest in understanding the effects of estrogen in the prostate also declined. Hormonal suppression of prostate cancer is now primarily achieved with androgen deprivation therapy (ADT) involving synthetic leutinising-hormone-releasing-hormone (LHRH) analogues, which suppress androgen production via negative feedback inhibition of the hypothalamic–pituitary–gonadal axis (Heidenreich et al. 2011). Although most prostate tumours initially respond well to ADT, after a period of time prostate cancer inevitably ceases to respond to androgen deprivation. Disease progression with ADT is termed castration-resistant prostate cancer (CRPC) (Scher et al. 2004), and is characterised by altered androgen receptor (AR) signalling. Possible mechanisms for this include amplification (Bubendorf et al. 1999) or mutation of the AR gene, stabilisation of AR protein (Holzbeierlein et al. 2004), altered expression of AR-coregulators (Chmelar et al. 2007), generation of constitutively active AR splice variants (Dehm et al. 2008, Hu et al. 2012) and increased intratumoural androgen biosynthesis (Cai & Balk 2011, Ishizaki et al. 2013), all of which contribute to the maintenance of AR-dependent transcription in a castrate environment (Knudsen & Penning 2010). Genome-wide mapping of AR DNA-binding has shown that in CRPC AR binds to new sites on the DNA, resulting in an alternative transcriptional programme to that seen in primary disease (Sharma et al. 2013). CRPC carries a poor prognosis and a median survival of 18 months from diagnosis (Wu et al. 2007). New generation chemotherapeutics agents targeting AR signalling such as abiraterone and enzalutamide have led to modest improvement in prostate cancer survival, but they are not curative (Attard et al. 2011, Lamb et al. 2013).
In recent years, with advances in the understanding of AR function in CRPC and the cross-talk that occurs between AR and estrogen receptor alpha (ERA) in prostate cancer (Grubisha & Defranco 2013) and specific subtypes of breast cancer (Robinson et al. 2011), there has been renewed interest in understanding ER biology in the prostate and its role in prostate cancer. Further interest has arisen as a result of recent phase 2 clinic trial evidence supporting the use of transdermal estrogen therapy in prostate cancer, which avoids first-pass liver metabolism and has an improved side-effect profile over both parenteral estrogens and LHRH analogues (Langley et al. 2013). It is now known that the prostate gland expresses both ERA and estrogen receptor beta (ERB) (Horvath et al. 2001, Celhay et al. 2010). ERB is expressed in a wide range of reproductive and non-reproductive tissues including the CNS, cardiovascular system, gastrointestinal tract, urogenital tract (male and female) and skeleton (Bottner et al. 2014). The physiological role of ERB in each of these tissues has not been fully elucidated, but it has been implicated in the regulation of glucose homeostasis and insulin signalling and may also modulate immunologically mediated inflammatory pathways (Harris et al. 2003, Foryst-Ludwig et al. 2008). In addition, ERB is considered a negative regulator of ERA, acting to modulate transcriptional responses to estrogen in a tissue- and cell-context dependent manner (Bottner et al. 2014).
The traditional paradigm regarding the roles of the two ERs in the prostate is that ERB is predominantly protective, being anti-carcinogenic and pro-apoptotic (Chang & Prins 1999, Horvath et al. 2001, Zhu et al. 2004, Ellem & Risbridger 2007, McPherson et al. 2010, Muthusamy et al. 2011, Nakajima et al. 2011, Attia & Ederveen 2012), whereas ERA is oncogenic and promotes cell proliferation and survival (Ellem & Risbridger 2007, Risbridger et al. 2007, McPherson et al. 2008, Bonkhoff & Berges 2009, Celhay et al. 2010, Attia & Ederveen 2012). This view is based on a range of observations including epidemiological and in vivo studies, preclinical drug trials and expression profiles of the two ERs in human prostate cancer. However, much of the published data regarding the role and function of ERB appear to be conflicting, with studies conducted in cancer cell lines (McPherson et al. 2010, Dey et al. 2012, Yang et al. 2012), rodent models (Ricke et al. 2008, Attia & Ederveen 2012) or human tissues (Horvath et al. 2001, Celhay et al. 2010, Leung et al. 2010, Hussain et al. 2012) generating apparently contradictory results. Thus the precise actions of ERB in the prostate remain to be completely elucidated (Shaaban et al. 2003, Risbridger et al. 2007, Zhao et al. 2007, Celhay et al. 2010, Nelles et al. 2011, Dey et al. 2012, Yang et al. 2012). In this article, we review recent research in the area of ERB biology, with particular attention to its relevance in clinical aspects of human prostate cancer, and highlight areas for future research.
Evidence for the role of estrogen in prostate cancer: epidemiological
It is well established that European men have a lower risk of developing prostate cancer than African-American men, and that for Japanese men the lifetime risk of developing prostate cancer is lower still (de Jong et al. 1991, Ross et al. 1992, Ellem & Risbridger 2007). Two interesting observations are noteworthy in this respect. First, there are no significant differences in levels of circulating testosterone between these three ethnic groups (Ross et al. 1992), whereas levels of serum estrogens are higher in black men as compared with Caucasian men (Rohrmann et al. 2007, Abd Elmageed et al. 2013). However, a direct correlation between serum estrogen levels and prostate cancer risk has not been demonstrated (Yao et al. 2011, Bosland 2013). Secondly, the age of peak prostate cancer incidence occurs at a time when serum testosterone levels are in decline, but estrogen levels remain constant (Vermeulen et al. 2002). This has lead to the hypothesis that it is the ratio of serum estrogen to testosterone, rather than the absolute values of each, which gives rise to the observed differences in prostate cancer risk between the various ethnic groups (Ellem & Risbridger 2007, Bosland 2013). However, recent technological advances, which now permit more accurate measurement of both ultra-low and intra-tissue hormone levels, mean that a contemporary reassessment of this subject is needed (Barth et al. 2010, Hickey & Norman 2010, Stener-Victorin et al. 2010). Determining the actual levels of estrogen and androgen metabolites in the prostate will be essential for understanding ERA, ERB and AR behaviour. Racial differences in levels of prostatic ERB expression as measured by immunohistochemistry have been demonstrated by Abd Elmageed et al. (2013) who showed that the frequency of ERB immunostaining in prostate tumours was significantly higher in black men than in Caucasian men, which in turn, correlated with poorer clinical outcome.
Estrogen-related prostate cancer risk has been linked to dietary factors (Hori et al. 2011). The traditional Japanese diet contains high levels of dietary phytoestrogens, which have been shown in prostate cancer cell lines to upregulate ERB activity resulting in decreased expression of AR (Thelen et al. 2005, 2007, Stettner et al. 2007) and induction of G1-cell cycle block (Shen et al. 2000). In rat models, phytoestrogens can induce prostate epithelial cell apoptosis (Attia & Ederveen 2012), thereby demonstrating protective effects against prostate cancer. Phytoestrogens, along with other dietary estrogens such as lignans, flavonoids and lipoflavinoid are known to have up to 30-fold greater affinity for ERB than ERA, and are thought to promote the beneficial, protective effects of estrogen in the prostate (Kuiper et al. 1998, Ellem & Risbridger 2007, Thelen et al. 2014). A large population-based case–control study from Sweden demonstrated a reduced incidence of prostate cancer in those with a diet rich in phytoestrogens (Hedelin et al. 2006). Incidence of prostate cancer in Japan has been rising since the 1940s, coinciding with increased ‘westernisation’ of the Japanese diet. Specifically, it has been proposed that the 20-fold increase in the consumption of milk and animal fat, both of which contain estrogens with a high affinity for ERA (mediating the adverse effects of estrogen) may explain some of the recent rise in prostate cancer incidence among Japanese men (Ganmaa et al. 2003, Carruba 2007). There are, however, conflicting results in the literature regarding the effects of phytoestrogens in prostate cancer, as genistein (a highly ERB-specific isoflavone (Jiang et al. 2013)) has been shown in a study of prostate cancer xenograft-bearing mice to promote the development of metastatic disease progression in an ERB-dependent manner (Nakamura et al. 2013) (discussed further in section ‘Evidence for the role of estrogen in prostate cancer: drug trials’).
Evidence for the role of estrogen in prostate cancer: animal studies
Some of the most compelling evidence for the importance of estrogen in prostate carcinogenesis comes from a series of animal studies (Ricke et al. 2008) (Fig. 1). Ricke et al. demonstrated in mice that androgen, estrogen, aromatase and ERA are all required for prostate carcinogenesis. Aromatase is a highly substrate-specific cytochrome p450 enzyme, found in the membrane of the endoplasmic reticulum, which has the unique function in vertebrates of being able to convert androgens to estrogens (Ghosh et al. 2009). In normal prostate, aromatase is expressed in the stromal cells and is responsible for local paracrine conversion of androgen to estrogen (Risbridger et al. 2007).
Summary of animal studies conducted by Ricke et al. (2008), demonstrating: (A) in order for prostate intraepithelial neoplasia (PIN) to arise it is necessary for androgen, estrogen and functional aromatase all to be present; (B) this is an ERA-mediated process, which is suppressed by ERB. ArKO, aromatase knockout; aERKO, ERA knockout; bERKO, ERB knockout.
Citation: Endocrine-Related Cancer 21, 4; 10.1530/ERC-13-0508
The necessity for estrogen in prostate carcinogenesis was demonstrated in experiments where either androgen alone, or androgen and estrogen were administered to aromatase knockout (ArKO) mice (Ricke et al. 2008). ArKO mice given androgen and estrogen developed prostatic intraepithelial neoplasia (PIN – a premalignant histological phenotype which, especially when high grade or multifocal, is a recognised risk factor for the development of invasive prostate cancer (Nelson et al. 2003, Merrimen et al. 2009)), whereas ArKO mice given androgen alone had no such change (Ricke et al. 2008). From this, the authors concluded that local production of estrogen within the prostate, facilitated by aromatase-mediated conversion of androgen to estrogen, was likely to be a significant factor in prostate carcinogenesis. Epithelial expression of aromatase is upregulated in prostate cancer (Ellem et al. 2004, Celhay et al. 2010), a process that is driven by gene promoters (I.3, I.4 and PII) responsive to inflammatory cytokines (Santen et al. 1997, Zhao et al. 1997, Shozu et al. 2000). The implication of this is twofold; first, increased local production of estrogens with resulting carcinogenesis and, secondly, the establishment of a ‘positive feedback loop’ between aromatase, estrogen and tissue inflammation (Ellem & Risbridger 2007). Indeed, high expression levels of aromatase and aromatase gene polymorphisms in early onset primary human prostate cancer have been found to correlate with decreased time to disease relapse, further underlining its importance in prostate carcinogenesis (Cussenot et al. 2007, Celhay et al. 2010).
In order to determine which of the ERs is responsible for mediating adverse effects of estrogen, Ricke et al. (2008) administered testosterone and estrogen to ERB knockout (bERKO) or ERA knockout (aERKO) mice. There was no difference between wild type (WT) and bERKO mice receiving hormone treatment, whereas aERKO mice did not develop PIN, suggesting that ERA mediated this particular adverse effect of estrogen in the prostate (Ricke et al. 2008). Similar studies in intact rats demonstrated that testosterone alone is insufficient for the development of PIN; it was only with the addition of the selective ERA agonist, ERA-45, that PIN developed (ERA-45 is reported to have a 286-fold greater affinity for ERA than ERB (Attia & Ederveen 2012)). However, with the administration of testosterone, ERA-45 and an ERB-selective agonist (ERB-26), the onset of PIN was prevented (Attia & Ederveen 2012), demonstrating the differential function of the two ERs in prostate carcinogenesis. These findings must be interpreted with some caution due to the ongoing debate in the field regarding the phenotypic variability and validity of the bERKO mouse models used in previous studies (Harris 2007).
Evidence for the role of estrogen in prostate cancer: drug trials
ERs are attractive targets for prostate cancer treatment as therapeutic agents are already in existence and are widely used in hormone-dependent breast cancer (Lumachi et al. 2011). Raloxifene, a selective ER modulator (SERM), has been shown to induce cellular apoptosis and nuclear fragmentation in both androgen-sensitive and androgen-independent prostate cancer cell lines through activation of ERB, suppression of ERA and subsequent induction of the caspase-8 and -9 pathways (Kim et al. 2002a,b, Rossi et al. 2011). Studies of selective ERB agonists on prostate cancer cell lines have also been encouraging. Several investigators have demonstrated that selective ERB agonists will induce cystic atrophy in basal cells of the prostatic epithelium (McPherson et al. 2010, Hussain et al. 2012). These basal cells do not express AR (Ruizeveld de Winter et al. 1991), and therefore, are unaffected by conventional ADT. Thus, once ADT is withdrawn, the prostatic epithelium is able to regenerate from this basal cell population. Administration of an ERB agonist, however, perturbs this regenerative process resulting in cellular apoptosis via the extrinsic pathway, mediated by tumour necrosis factor α (TNFA). This, importantly, is an androgen-independent process and may therefore be relevant to the treatment of CRPC (McPherson et al. 2010, Hussain et al. 2012). Recent research has shown that ERB-mediated cellular apoptosis may also occur through the intrinsic pathway, via upregulation of the Forkhead protein, FOXO3a, which itself is regulated by PTEN. Deletion mutations of PTEN result in inhibition of the apoptotic mechanism of FoxO3a, providing a possible ERB-mediated mechanism by which PTEN mutations in prostate cancer contribute to cancer growth (Dey et al. 2013b).
In vitro studies of the effects of dietary phytoestrogens on prostate cancer cell lines have shown conflicting results. On the one hand it has been shown that administration of ERB-selective phytoestrogens in CRPC will revert cancer cells to a less malignant phenotype (Wuttke et al. 2002, Messina 2010, Andres et al. 2011, Reiter et al. 2011). This may be due to a number of mechanisms. It is known that mutated forms of AR are upregulated in CRPC allowing AR to continue driving prostate cancer growth and progression in the absence of androgen (Scher et al. 2004, Waltering et al. 2012). Upregulation of ERB in response to phytoestrogens results in down-regulation of AR, with a subsequent decline in serum levels of prostate-specific antigen (PSA) and other AR-dependent genes (Thelen et al. 2005, 2007). ERB may therefore function as a negative regulator of AR, as well as ERA. However, as previously mentioned, in a study conducted using a patient-derived prostate cancer tissue line mouse xenograft model (maintained by serial transplantation of sub-renal capsule xenografts) (Andersen et al. 2010), the ERB-selective phytoestrogen genistein has been shown to promote development of metastatic disease (Nakamura et al. 2013). The explanation for these conflicting results is not presently clear; however it has been hypothesised that in the mouse xenograft tumours, increased expression of metallothionein proteins in response to genistein-induced ERB activity may contribute to tumour invasion and metastasis (Nakamura et al. 2013); an interaction, which may not be reflected in cell-line studies where the tumour microenvironment is absent.
A promising clinical study was published by Price et al. (2006). In a phase 2b clinical trial of 514 men with biopsy-proven high-grade PIN, toremifene, an ERA-selective antagonist (Kangas 1990), was shown to reduce the incidence of invasive prostate cancer at 12 months by 48% vs placebo, thus preventing 6.8% cancers per 100 men per year. However, the outcome of this trial was reported after only a 12-month study period and no long-term data on the use of toremifene in prostate cancer have since been generated to address potential long-term side effects or duration of treatment benefit.
Trials of other ER modulators have also been unsuccessful. Fulvestrant, an ERA antagonist, has been shown to be effective in preclinical models with growth inhibition of prostate cancer cell lines (Lau et al. 2000, Leung et al. 2006a). However, in a phase 2 study of 20 men with CRPC, fulvestrant failed to produce either a clinical or biochemical (PSA) response (Chadha et al. 2008). Similarly, tamoxifen, a mixed ERA agonist/antagonist has been shown to be ineffective in men with CRPC (Bergan et al. 1999) despite inhibiting the growth of prostate cancer cell lines in preclinical studies (Rohlff et al. 1998). The reasons underlying these observations are not presently clear; however, it is likely that prostate cancer cell lines used in the preclinical studies are not reflecting the complex cross-talk between AR, ERA and ERB, and other stromal–epithelial interactions known to occur in vivo (Hanahan & Weinberg 2011, Robinson et al. 2011, Grubisha & Defranco 2013, Madak-Erdogan et al. 2013). These studies highlight the critical need for improved preclinical models of prostate cancer, in which to test new therapeutic agents targeted to the ERs.
ERs in the prostate
ERB was first identified by Kuiper et al. (1996) in the rat prostate. In humans, it is a 55 kDa protein encoded by the ESR2 gene located on chromosome 14 (Enmark et al. 1997). Expression of ERB is regulated epigenetically by a CpG island in the promotor region (Zhu et al. 2004) and ERB expression is silenced by DNA-hypermethylation of the promotor (Zhao et al. 2003, Rody et al. 2005). ERB is strongly expressed in the basal and secretory compartments of benign prostate epithelium in both rodents and humans (Horvath et al. 2001). The principle ligand of ERB in the prostate is 5α-androstane-3β,17β-diol (3β-diol), a metabolite of 5α-dihydrotestosterone (DHT) (Oliveira et al. 2007). In prostate cell lines (benign and cancer) ERB has been shown to maintain differentiation of epithelial cells by regulation of epithelial–mesenchymal transition (EMT) genes such as Twist via hypoxia-inducible factor 1 alpha (HIF-1A) (Mak et al. 2013).
The gene coding human ERA (ESR1) is located on chromosome 6 (Menasce et al. 1993). In the prostate (rodent and human) ERA is predominantly expressed in the stroma (Celhay et al. 2010, Attia & Ederveen 2012). In utero studies of prostate development in rodents have shown that ERA expression appears before ERB, and excessive estrogenisation of the developing prostate (mediated via ERA) results in permanent changes in the prostate including squamous metaplasia, inflammation and epithelial dysplasia (Arai et al. 1978, Prins & Birch 1997). This ‘imprinting’ results in increased risk of a premalignant phenotype and prostate carcinogenesis (Prins et al. 2006, 2007, McPherson et al. 2008, Prins & Korach 2008). Although expressed from different genes, ERA and ERB share substantial sequence homology, in particular the DNA-binding domains (DBD) of the two receptors are 97% identical. This allows both ERs to recognise a consensus estrogen response element (ERE) on DNA with equal affinity (Le et al. 2013).
The advent of genome-wide transcription factor mapping by chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) has enabled detailed study of how transcription factors such as steroid hormone receptors function, by revealing the locations of their DNA-binding sites (Carroll et al. 2006). We now know, for example, that in addition to proximal gene promotors, ERA and AR bind to distal enhancer elements, far from gene-transcription start sites, and by recruitment of co-regulatory factors initiate gene transcription by long-range chromatin interactions (Carroll et al. 2005, Wang et al. 2007, Massie et al. 2011). For ERA and AR, a number of these co-regulatory factors are now well-characterised and represent potential therapeutic targets (Carroll et al. 2005, Wang et al. 2007, 2009, 2011, Hurtado et al. 2011, Robinson et al. 2011, Sahu et al. 2011). Genome-wide mapping of both tagged (Zhao et al. 2010) and force-expressed recombinant ERB (Madak-Erdogan et al. 2013) DNA-binding in the MCF7 breast cancer cell line has demonstrated significant overlap between ERA and ERB DNA-binding sites, inferring complex cross-talk between the two receptors. In addition, there is evidence that ERB binds to distal enhancer elements in the same manner as ERA and AR to regulate gene expression (Carroll et al. 2005, Zhao et al. 2010, Massie et al. 2011). Despite these significant insights, there is still very limited understanding of the mechanisms and co-regulators by which ERB activity may be modulated and thus the resulting effects on ERB transcription.
ER expression in prostate cancer
In normal prostate, ERA expression is confined to the prostatic stroma (Tilley et al. 1985, Wernert et al. 1988, Leav et al. 2001). In contrast to ERB, ERA mRNA has been detected in high-grade PIN of the prostate, and ERA expression is upregulated in prostatic epithelium of intermediate- and high-grade tumours and in CRPC (Bonkhoff & Berges 2009, Celhay et al. 2010, Nelles et al. 2011). Stromal ERA expression and elevated expression of aromatase have been shown to be independent predictors of shorter time to relapse in CRPC (Celhay et al. 2010). Expression of the TMPRSS2–ERG fusion gene, which has been suggested to be a marker of an aggressive tumour phenotype found in up to 50% of prostate cancer (Qu et al. 2013, Razzak 2013), increased in the NCI-H660 prostate cancer cell line following treatment with an ERA agonist (Setlur et al. 2008). NCI-H660 is an AR-negative prostate cancer cell line expressing the TMPRSS2-ERG fusion gene (Mertz et al. 2007), derived from the lymph node metastasis of a small-cell prostate tumour with neuroendocrine differentiation (Johnson et al. 1989, Lai et al. 1995). Expression of ERA and aromatase with the R264C polymorphism has been shown to result in shorter progression-free survival and an increased risk of developing CRPC in a study of 115 men treated with docetaxel (Sissung et al. 2011). Taken together, these observations support the hypothesis that ERA can act as an oncogene by mediating the adverse effects of estrogen in the prostate.
Declining levels of ERB have been observed with progression from benign prostatic hyperplasia to malignant disease (Horvath et al. 2001), with a further decrease associated with increasing Gleason grade of prostate cancer (Leav et al. 2001, Asgari & Morakabati 2011, Attia & Ederveen 2012, Dey et al. 2013b). ERB expression is low in high-grade PIN of the prostate (Risbridger et al. 2007), reflecting its pre-malignant phenotype. It has been shown that as ERB expression declines with the development of prostate cancer, levels of HIF-1A increase, resulting in epithelial de-differentiation and growth of high-grade, aggressive tumours (Mak et al. 2013).
Horvath et al. (2001) showed in a study of 159 prostates obtained by radical prostatectomy that over 75% of tumours in their cohort did not express ERB. However, in low-grade (Gleason 3) tumours, ERB expression was maintained, and correlated positively with disease-free survival (Horvath et al. 2001). In an additional finding that seems to contradict these results, where ERB expression was maintained, there was a higher rate of disease relapse irrespective of tumour grade (Horvath et al. 2001). Other studies have demonstrated high ERB expression in bone and lymph node metastases (Zhu et al. 2004, Bouchal et al. 2011). A recent study has shown that the combination of ERB expression and AR phosphorylation in hormone-naïve prostate cancer correlates with poor clinical outcome (Zellweger et al. 2013). In that study, increased expression of WT ERB (ERB1) was associated with higher Gleason grade and greater proliferative activity. Fifty percent of the patients in the study cohort showed a significant increase in ERB expression with subsequent development of CRPC (Zellweger et al. 2013).
The variability of ERB expression in differing grades and stages of prostate cancer presents some difficulty in deciphering the underlying mechanisms and role of ERB in prostate carcinogenesis. If ERB is tumour-suppressive, then it is logical that its expression declines with advancing carcinogenesis. However, this does not explain why ERB expression is then high in lymph node or bone metastases ( Zhu et al. 2004, Bouchal et al. 2011), or the observed correlation between high ERB expression and poor prostate cancer prognosis (Horvath et al. 2001, Zellweger et al. 2013). This may be due to varying levels of promotor methylation throughout the carcinogenic process introducing reversible, stage- and tissue-specific changes in ERB expression and altering its transcriptional role (Risbridger et al. 2007, Cotrim et al. 2013). In addition, it has been proposed that ERB expression may confer a selective advantage for subclones of prostate cancer cells to metastasise (Zhu et al. 2004), resulting in the maintenance of ERB expression in metastatic deposits. A further possible explanation for this discrepancy is variability in the specificity and sensitivity of commercially available ERB antibodies (Skliris et al. 2002, Hartman et al. 2012). Different ERB antibodies have been shown to only be suitable for particular experimental applications (Weitsman et al. 2006), creating some difficulty in the interpretation of results from different studies.
More recently, there is increasing evidence that expression of the ERB isoform, ERB2, is increased in high-grade and metastatic prostate cancer (Dey et al. 2012). ERB2 may act as an oncogene and has been implicated specifically in the process of cancer metastasis (Chen et al. 2009, Leung et al. 2010, Dey et al. 2012). If the antibodies used in the abovementioned studies (Horvath et al. 2001, Zhu et al. 2004, Bouchal et al. 2011, Zellweger et al. 2013) are in fact detecting ERB2, rather than ERB1, some of the abovementioned contradictions may be explained. Further detailed study is required to answer this definitively.
The role of ERB isoforms
At least five splice variants of ERB have been identified (Leung et al. 2006b) (Fig. 2). Expression of ERB3 is limited to the testis (Moore et al. 1998), but ERB1, ERB2, ERB4 and ERB5 are known to be expressed in the prostate, and there is increasing evidence indicating that ERB2 in particular acts as an oncogene in direct opposition to ERB1 (Chen et al. 2009). ERB1 is composed of eight exons, the first six of which are common to the five isoforms. The isoforms share the same first four functional domains with ERB1 (including the DBD), but the LBD differs (Moore et al. 1998, Hanstein et al. 1999, Leung et al. 2010). ERB2 and ERB5 have been studied in detail in prostate cancer and shown to correlate with poor prognosis (Leung et al. 2010, Dey et al. 2012). Specifically, co-expression of nuclear ERB2 and cytoplasmic ERB5 was shown in a study of 144 patients with long-term follow up to be an independent prognostic marker for biochemical relapse, postoperative metastasis and time to metastasis following radical prostatectomy for localised prostate cancer (Leung et al. 2010). While ERB2 is the dominant isoform in prostate cancer, its mechanism of action remains unclear as it lacks the LBD. ERB2 seems to act as a transcriptional repressor of ERB1, thus disabling the usual, protective effect of ERB1 (Cotrim et al. 2013). One hypothesis proposed by Leung et al. (2006b) is that whilst ERB1 functions as a homodimer, ERB isoforms function only when heterodimerised with ERB1. These ERB heterodimers form preferentially under the influence of oestradiol (E2) and have higher transcriptional activity than the ERB1 homodimer. Interestingly, phytoestrogens such as genistein promote formation of the ERB1 homodimer. As ERB2 lacks a LBD, it is proposed that when it is heterodimerised with ERB1, transcription is inhibited. In this model, ERB2 may therefore function as a dominant-negative regulator of ERB1 activity. This may explain one way that ERB transcription can be modulated in cell- and tissue-specific contexts (Leung et al. 2006b, Cotrim et al. 2013).
Schematic showing the structure of ERB isoforms. ERB1 (WT) contains eight exons, the first six of which are common to the other isoforms. All five isoforms share common DNA-binding domains (DBD), but the ligand-binding domains (LBD) differ. Data from Uniprot (http://www.uniprot.org/) and ClustalW2 (http://www.ebi.ac.uk/Tools/msa/clustalw2/).
Citation: Endocrine-Related Cancer 21, 4; 10.1530/ERC-13-0508
In ovarian carcinoma, levels of ERB5 mRNA are elevated, compared with benign tissues, suggesting it has an oncogenic role in that particular context (Suzuki et al. 2008). A study of stable tetracycline-inducible ERB2-expressing MCF7 breast cancer cells has suggested that ERB2 can also heterodimerise with ERA to induce ERA degradation and inhibition of ERA transcription (Zhao et al. 2007).
The influence of ERB2 in both prostate and breast cancer metastasis is thought to result from regulation of genes responsible for EMT (Leung et al. 2010, Dey et al. 2012, Roy et al. 2012, Yang et al. 2012). EMT is a marker of early oncological change, which enables cancer cells to invade surrounding tissues and eventually metastasise to distant sites (Hanahan & Weinberg 2011). Although well-characterised in vitro, there is still some controversy as to whether the EMT programme occurs in vivo or is an artefact of cell line studies, principally because of difficulties differentiating transformed epithelial cells from the surrounding tumour stromal tissue, and the fact that metastatic deposits often closely resemble the epithelial tissue of origin (Hollier et al. 2009). Nevertheless, evidence is emerging that EMT markers can be observed in circulating tumour cells, suggesting that it does occur in vivo (Li et al. 2013).
In a study conducted in prostate cancer cell lines, expression of ERB2 was shown to result in upregulation of the EMT genes TWIST1 (which correlates with high-grade prostate cancer) and RUNX2 (normally repressed by ERB1) (Dey et al. 2012). This interaction between ERB2 and EMT genes is facilitated by a proto-oncogene, PELP1, which interacts with a number of steroid hormone receptors including ERA (Vadlamudi et al. 2001), ERB and AR (Yang et al. 2012). In breast cancer, PELP1 has been shown to interact with histones to remodel chromatin and modulate expression of key EMT genes such as TWIST1, SNAIL and ZEB (Roy et al. 2012). It is therefore possible that PELP1 and ERB2 have a role in the promotion of prostate cancer metastasis. If correct, this hypothesis could explain the previously discussed findings of high ERB expression in bone and lymph node metastases, and the correlation between persistent ERB expression in high-grade prostate cancer and greater risk of disease relapse (Horvath et al. 2001, Zhu et al. 2004, Bouchal et al. 2011, Zellweger et al. 2013). This is an important area for further investigation.
The role of ER-mediated inflammation in mechanisms of cancer progression
Inflammation is a well-established process in the development and progression of cancer (Hanahan & Weinberg 2011) (Fig. 3). Several inflammatory mechanisms, centering on ER function, have been implicated in the development and progression of prostate cancer. Loss of E-cadherin is a well-established marker of EMT, with associated loss of cell adhesion and a resulting increase in cell motility (Guarino et al. 2007, Grubisha & Defranco 2013). ERB has been shown to be a negative regulator of inflammatory processes (Harris et al. 2003) and in the prostate its expression is known to correlate with E-cadherin levels. One hypothesis is that as ERB expression declines during the progression from benign to low-grade, to high-grade cancer (Leav et al. 2001, Celhay et al. 2010, Asgari & Morakabati 2011), the resulting decline in E-cadherin leads to an increased propensity to develop metastatic disease. ERB transcriptional activity is sensitive to oxidation resulting from tissue inflammatory processes and a local paracrine signalling network (Grubisha et al. 2012). When ERB is oxidised by H2O2 and other reactive oxygen species, DNA binding is lost and expression of E-cadherin is reduced. The pro-inflammatory enzyme COX2, expressed by prostatic stroma, generates sufficient H2O2 to inactivate ERB. As COX2 is overexpressed in prostate cancer, a pro-inflammatory positive feedback loop is established (Grubisha & Defranco 2013).
Proinflammatory positive feedback loops in prostate cancer progression, centering on ERB and ERA function. In response to tissue inflammation, decreased ERB expression results in upregulation of EMT programme genes leading to prostate cancer metastasis. Tissue inflammation leads to increased aromatase expression and increased inflammatory-cell epithelial infiltration. Decreased ERB transcription results in loss of direct repression of ERA. WBC, white blood cell; E2, oestradiol; NO, nitric oxide; H2O2, hydrogen peroxide; COX2, cyclo-oxygenase-2; PCa, prostate cancer.
Citation: Endocrine-Related Cancer 21, 4; 10.1530/ERC-13-0508
ERA and aromatase also play a critical role in tissue inflammation in prostate cancer and expression of these two factors in tumour cells is an independent predictor of time to biochemical relapse (defined as two consecutive rises in serum PSA) in men treated with ADT (Celhay et al. 2010). In prostate cancer, expression of aromatase is increased, particularly in epithelial cells resulting in increased levels of intraprostatic estrogen, which acts via ERA to promote tissue inflammation via local generation of nitric oxide (Pinzone et al. 2004, Ellem & Risbridger 2007, Risbridger et al. 2007, Celhay et al. 2010, Nelles et al. 2011). Pro-inflammatory mediators such as TNFA and prostaglandin E2 in turn upregulate CYP19 expression, resulting in increased aromatase activity (Subbaramaiah et al. 2011). Thus an additional pro-inflammatory positive feedback loop centering on ERA function is established (Ellem & Risbridger 2007). Evidence of neutrophil and leucocyte migration from the stroma to the epithelium in mouse models confirms the presence of this inflammatory process (Bianco et al. 2002, 2006). Inflammatory cytokines released by the migrating immune cells result in abnormal proliferation of prostate epithelium and increase the risk of further premalignant change (Bianco et al. 2006).
A change in perspective: an oncogenic role for ERB?
ERB1 has been implicated directly as an oncogene (Yang et al. 2012). In that study, ERB1-mediated, non-androgenic AR signalling was demonstrated in several prostate cancer cell lines in hormone-deplete (castrate) conditions (Fig. 4). In the presence of DHT, AR binds to androgen-responsive elements (AREs) on DNA to initiate AR-dependent transcription. In these conditions, ERB1 and PELP1 form a complex in the nucleus. However, in the absence of DHT and with addition of E2, the ERB1–PELP1 complex binds to AR (with PELP1 acting as a bridge between the two nuclear receptors) and is recruited to an ARE, resulting in the transcription of AR-dependent genes. This ERB1–PELP1–AR complex was shown to facilitate cellular proliferation in response to E2 treatment, demonstrating a clear mechanism by which estrogens might continue to drive prostate cancer growth and progression in the castrate environment, thereby highlighting the potential oncogenic role of ERB1. Furthermore, it has been proposed that ERB1 may have a role in mediating the ‘switch’ from hormone-sensitive prostate cancer to CRPC (Zellweger et al. 2013). It may be that ERB is only tumour-suppressive in early stages of the disease until, by means of a currently unknown mechanism, it subsequently becomes an oncogene. This is an important question for detailed investigation, as therapeutic silencing of such a ‘switch’ could theoretically reduce the risk of developing CRPC.
A hypothesis of non-androgenic, ERB-mediated transcription of AR-dependent genes via interaction with PELP1, as proposed by Yang et al. (2012). (A) In the presence of DHT ERB-PELP1 forms a complex, which does not bind to AR. (B) In the absence of DHT, and with oestradiol (E2) treatment, the ERB-PELP1-AR complex binds to the androgen-responsive element (ARE) to initiate AR-dependent gene transcription. Figure adapted from Yang L, Ravindranathan P, Ramanan M, Kapur P, Hammes SR, Hsieh JT & Raj GV 2012 Central role for PELP1 in nonandrogenic activation of the androgen receptor in prostate cancer. Molecular Endocrinology 26 550–561.
Citation: Endocrine-Related Cancer 21, 4; 10.1530/ERC-13-0508
Our understanding of the role of ERB in the development and progression of prostate cancer is evolving, but there are many unresolved issues. Given the divergent activity of ERB isoforms and the potential for an oncogenic role for ERB1 (Yang et al. 2012), we can no longer hold to the classical paradigm of estrogen signalling in the prostate, which surmises that ERA is tumour promoting and ERB is tumour suppressive. In order to progress our understanding of estrogen biology in cancer it is critical that the mechanisms underlying the differential functions of ERA, ERB and the various ERB isoforms are elucidated in detail (Madak-Erdogan et al. 2013). Recent advances in understanding the function of the two ERs at the genomic level have been beginning to provide insights into this complex area. Madak-Erdogan et al. (2013) used ChIP-seq to demonstrate the genome-wide chromatin binding profiles and differing transcriptional responses of ERA or ERB in the MCF7 breast cancer cell line. Their data confirmed the previous finding using the tagged ERB ChIP-seq approach (Zhao et al. 2010) demonstrating significant overlap between the binding sites of ERA and ERB. Specifically, when each of the receptors was present alone, there was a 40% overlap between ERA and ERB DNA-binding sites. However, when co-expressed, the number of binding sites available for each ER dropped by ∼50%. This suggests a complex mechanism where each ER restricts the total number of binding sites available to the other, but when the activity of one ER is reduced, chromatin binding by the other is increased. While the functional consequences of altered ERA and ERB chromatin binding in these different contexts remain to be fully elucidated, the proliferative effects of estrogen acting via ERA were reduced with the co-expression of ERB. When expressed in isolation, ERA regulates cell cycle genes, helping push cells from growth-arrested states into DNA synthesis and subsequent mitosis. However, when ERB is co-expressed, ERA's ability to respond to ligand is reduced and cell proliferation decreases. ERB's anti-proliferative function was demonstrated to occur through direct binding to apoptosis and cell-cycle regulation genes (Madak-Erdogan et al. 2013). Similar results were demonstrated by Le et al. (2013) in ChIP-seq of MCF7/C4-12 cells (derivative of MCF7 with no ERA expression) transfected to stably express ERB. These data support the previously discussed hypothesis that ERB is tumour-suppressive and a negative regulator of ERA, functioning in a variable manner according to the particular cellular context (Zhao et al. 2010, Bottner et al. 2014, Cotrim et al. 2013). However, as these data were generated using breast cancer cell lines, it is important that the hypothesis is further tested in appropriate prostate cancer models. The isoform specificities of the antibodies used in the ChIP-seq study (Madak-Erdogan et al. 2013) are unknown and therefore it is not clear how these findings in MCF7 cells are applicable to the previously discussed differential functions of ERB isoforms (Leung et al. 2010, Dey et al. 2012). Clearly, there is an urgent need to develop specific antibodies to ERB and its isoforms to address these questions (Haldosen et al. 2014).
Conclusions
Despite a number of promising preclinical studies showing efficacy of ERB-selective agents in prostate cancer (Kim et al. 2002a,b, McPherson et al. 2010), there is currently no evidence of clinical benefit from the use of these treatments in terms of disease-specific or overall survival. The underlying reasons for this necessitate further investigation. One possibility is insufficient dosing of the therapeutic agents in question (Chadha et al. 2008). Most of the preclinical studies of ERB-selective agents and much of our current knowledge of ERB biology results from studies conducted in various prostate cancer cell lines. The expression profiles of the nuclear receptors AR, ERA and ERB vary between each of the commonly used cell lines and different authors report contrasting results in individual cell lines (Table 1) (Veldscholte et al. 1990, Kim et al. 2002b, Holbeck et al. 2010, Nakajima et al. 2011). None of these commonly used cell lines are entirely representative of human tissue, as exemplified by the fact that in the human prostate ERA expression is predominantly stromal, whereas luminal epithelial cells express ERB and AR, and basal epithelial cells only express ERB (Ruizeveld de Winter et al. 1991, Bonkhoff & Berges 2009). Cell line models, therefore, cannot reproduce the stromal–epithelial interactions known to be important in cancer development and progression (Hanahan & Weinberg 2011), or the complex interplay that has been observed between ERA and ERB, and how transcription from activation of one receptor impacts the availability of DNA-binding sites to the other (Madak-Erdogan et al. 2013). Studies conducted in ex vivo primary human tissue culture (Centenera et al. 2012) or xenografts of human tumours (Lawrence et al. 2013) may be helpful in this regard.
Variability of reported nuclear receptor expression in commonly used prostate cancer cell lines
| References | Cell line | AR | ERA | ERB |
|---|---|---|---|---|
| Veldscholte et al. (1990) and Kim et al. (2002a,b) | LNCaP | Positive (mutant) | Negative | Positive |
| Nakajima et al. (2011) | DU145 | Negative | Negative | Positive |
| Holbeck et al. (2010) | DU145 | Negative | Negative | Negative |
| Holbeck et al. (2010) and Nakajima et al. (2011) | PC3 | Negative | Positive | Positive |
Estrogen-related pathways are clearly of great importance in the development and progression of hormone-dependent cancers such as prostate cancer, but the role of ERB remains controversial, with numerous contradictions in the published literature. Our current understanding of ER biology in the prostate is insufficient to facilitate precise manipulation of the molecular machinery in a meaningful fashion (Abd Elmageed et al. 2013). Recent developments in the understanding of apparently opposing ERB isoforms (Leung et al. 2010) and the mechanisms governing ERB transcription are beginning to provide greater insights into ERB biology with implications not just for prostate cancer but also for colon, breast and ovarian cancers (Suzuki et al. 2008, Chantzi et al. 2013, Dey et al. 2013a). In order to determine whether ERB represents a useful therapeutic target in prostate cancer, and more specifically in CRPC, it is vital that these mechanisms are fully elucidated. Given that ERA and ERB can homo- or heterodimerise with ERB isoforms, the cross-reactivity between different estrogenic ligands, the differing effects of ERB in specific cellular contexts, and the fact that ERA and ERB can recognise the same DNA-binding sites and interact with common co-regulators, this is likely to be a difficult task (Shaaban et al. 2003, Zhao et al. 2010, Cotrim et al. 2013, Le et al. 2013, Madak-Erdogan et al. 2013). The challenge will be to identify and characterise the ERA- and ERB-unique DNA-binding sites, and furthermore, to define the ERB isoform-specific DNA binding sites in order to determine their respective functions. To improve outcomes for patients, there is an urgent need for detailed understanding of the mechanisms governing the differential functions of the two ERs in tissue- and disease-specific contexts as well as investigation of novel therapeutic agents that selectively target ERA- and ERB-dependent pathways.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.
Funding
A W Nelson is supported by The Medical Research Council (MR/L00156X/1) and The Urology Foundation Scholarship (RESCH1302); W D Tilley is supported by grants from the National Health and Medical Research Council of Australia (ID 627185), Cancer Australia (ID 627229) and the Prostate Cancer Foundation of Australia; D E Neal is supported by Cancer Research UK, The Medical Research Council and The National Institute for Health Research; J S Carroll is supported by an ERC starting grant and an EMBO Young investigator award.
Author contribution statement
A W Nelson and W D Tilley conceptualised and designed the structure of the article. A W Nelson conducted the literature review. A W Nelson and W D Tilley co-wrote the manuscript. D E Neal and J S Carroll provided critical review and revision of the manuscript.
Acknowledgements
A W Nelson is an Honorary Research Training Fellow of the Royal College of Surgeons of England/Prostate Cancer UK and acknowledges their support.
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