Estrogen Receptor ß4 Regulates Chemotherapy Resistance and Induces Cancer Stem Cells in Triple Negative Breast Cancer.

Triple Negative Breast Cancer (TNBC) has the worst prognosis among all breast cancers, and survival in patients with recurrence is rarely beyond 12 months due to acquired resistance to chemotherapy, which is the standard of care for these patients. Our hypothesis is that Estrogen Receptor ß1 (ERß1) increases response to chemotherapy but is opposed by ERß4, which it preferentially dimerizes with. The role of ERß1 and ERß4 in influencing chemotherapy sensitivity has never been studied before. CRISPR/CAS9 was used to truncate ERß1 Ligand Binding Domain (LBD) and knock down the exon unique to ERß4. We show that the truncated ERß1 LBD in a variety of mutant p53 TNBC cell lines, where ERß1 ligand dependent function was inactivated, had increased resistance to Paclitaxel, whereas the ERß4 knockdown cell line was sensitized to Paclitaxel. We further show that ERß1 LBD truncation, as well as treatment with ERß1 antagonist 2-phenyl-3-(4-hydroxyphenyl)-5,7-bis(trifluoromethyl)-pyrazolo[1,5-a] pyrimidine (PHTPP), leads to increase in the drug efflux transporters. Hypoxia Inducible Factors (HIFs) activate factors involved in pluripotency and regulate the stem cell phenotype, both in normal and cancer cells. Here we show that the ERß1 and ERß4 regulate these stem cell markers like SOX2, OCT4, and Nanog in an opposing manner; and we further show that this regulation is mediated by HIFs. We show the increase of cancer cell stemness due to ERß1 LBD truncation is attenuated when HIF1/2α is knocked down by siRNA. Finally, we show an increase in the breast cancer stem cell population due to ERß1 antagonist using both ALDEFLUORTM and SOX2/OCT4 response element (SORE6) reporters in SUM159 and MDA-MB-231 cell lines. Since most TNBC cancers are ERß4 positive, while only a small proportion of TNBC patients are ERß1 positive, we believe that simultaneous activation of ERß1 with agonists and inactivation of ERß4, in combination with paclitaxel, can be more efficacious and yield better outcome for chemotherapy resistant TNBC patients.

25 years of ERß: a personal journey.

Summary: After the discovery of ERß, a novel role for dihydrotestosterone (DHT) in estrogen signaling was revealed. Instead of just being a better androgen, DHT was found to be a precursor of the ERß agonist 5α-androstane-3ß, 17ß-diol (3ßAdiol), an estrogen which does not require aromatase for its synthesis. ERß was found to oppose androgen signaling and thus is a potential target for treatment of prostate cancer. ERß was also found to have effects that were independent of androgen signaling, particularly in the CNS. Although in rodent models of neurodegenerative diseases (Parkinson's disease, multiple sclerosis, and Alzheimer's disease), ERß agonists are very effective in relieving symptoms and improving pathologies, this has not proven to be the case in humans. In this review we will focus on the main differences in ERß signaling between rodents and humans and will make the point that a very important difference between the two species is in the splice variants which are expressed in humans and not rodents. The main conclusion at this point is that before we think of using ERß agonists clinically, much more work on ERß signaling in the human or in primates needs to be done.

Estrogen receptor ß regulates AKT activity through up-regulation of INPP4B and inhibits migration of prostate cancer cell line PC-3.

Loss of the tumor suppressor, PTEN, is one of the most common findings in prostate cancer (PCa). This loss leads to overactive Akt signaling, which is correlated with increased metastasis and androgen independence. However, another tumor suppressor, inositol-polyphosphate 4-phosphatase type II (INPP4B), can partially compensate for the loss of PTEN. INPP4B is up-regulated by androgens, and this suggests that androgen-deprivation therapy (ADT) would lead to hyperactivity of AKT. However, in the present study, we found that in PCa, samples from men treated with ADT, ERß, and INPP4B expression were maintained in some samples. To investigate the role of ERß1 in regulation of INPPB, we engineered the highly metastatic PCa cell line, PC3, to express ERß1. In these cells, INPP4B was induced by ERß ligands, and this induction was accompanied by inhibition of Akt activity and reduction in cell migration. These findings reveal that, in the absence of androgens, ERß1 induces INPP4B to dampen AKT signaling. Since the endogenous ERß ligand, 3ß-Adiol, is lost upon long-term ADT, to obtain the beneficial effects of ERß1 on AKT signaling, an ERß agonist should be added along with ADT.

Estrogen receptor ß exerts tumor suppressive effects in prostate cancer through repression of androgen receptor activity.

Estrogen receptor ß (ERß) was first identified in the rodent prostate and is abundantly expressed in human and rodent prostate epithelium, stroma, immune cells and endothelium of the blood vessels. In the prostates of mice with inactivated ERß, mutant phenotypes include epithelial hyperplasia and increased expression of androgen receptor (AR)-regulated genes, most of which are also upregulated in prostate cancer (PCa). ERß is expressed in both basal and luminal cells in the prostate while AR is expressed in luminal but not in the basal cell layer which harbors the prostate stem cells. To investigate the mechanisms of action of ERß and its potential cross-talk with AR, we used RNA-seq to study the effects of estradiol or the synthetic ligand, LY3201, in AR-positive LNCaP PCa cells which had been engineered to express ERß. Transcriptomic analysis indicated relatively few changes in gene expression with ERß overexpression, but robust responses following ligand treatments. There is significant overlap of responsive genes between the two ligands, estradiol and LY3201 as well as ligand-specific alterations. Gene set analysis of down-regulated genes identified an enrichment of androgen-responsive genes, such as FKBP5, CAMKK2, and TBC1D4. Consistently, AR transcript, protein levels, and transcriptional activity were down-regulated following ERß activation. In agreement with this, we find that the phosphorylation of the CAMKK2 target, AMPK, was repressed by ligand-activated ERß. These findings suggest that ERß-mediated signaling pathways are involved in the negative regulation of AR expression and activity, thus supporting a tumor suppressive role for ERß in PCa.

Oncogenic KRAS-Driven Metabolic Reprogramming in Pancreatic Cancer Cells Utilizes Cytokines from the Tumor Microenvironment.

A hallmark of pancreatic ductal adenocarcinoma (PDAC) is an exuberant stroma comprised of diverse cell types that enable or suppress tumor progression. Here, we explored the role of oncogenic KRAS in protumorigenic signaling interactions between cancer cells and host cells. We show that KRAS mutation (KRAS*) drives cell-autonomous expression of type I cytokine receptor complexes (IL2rγ-IL4rα and IL2rγ-IL13rα1) in cancer cells that in turn are capable of receiving cytokine growth signals (IL4 or IL13) provided by invading Th2 cells in the microenvironment. Early neoplastic lesions show close proximity of cancer cells harboring KRAS* and Th2 cells producing IL4 and IL13. Activated IL2rγ-IL4rα and IL2rγ-IL13rα1 receptors signal primarily via JAK1-STAT6. Integrated transcriptomic, chromatin occupancy, and metabolomic studies identified MYC as a direct target of activated STAT6 and that MYC drives glycolysis. Thus, paracrine signaling in the tumor microenvironment plays a key role in the KRAS*-driven metabolic reprogramming of PDAC. SIGNIFICANCE: Type II cytokines, secreted by Th2 cells in the tumor microenvironment, can stimulate cancer cell-intrinsic MYC transcriptional upregulation to drive glycolysis. This KRAS*-driven heterotypic signaling circuit in the early and advanced tumor microenvironment enables cooperative protumorigenic interactions, providing candidate therapeutic targets in the KRAS* pathway for this intractable disease.

Update on ERbeta.

ERbeta (ERß) celebrated its 20th birthday in 2016 and although the overwhelming data in the literature indicate a role for this receptor in the control of epithelial proliferation, neurodegeneration and immune function, no ERß agonists have yet made it to the clinics. This is the situation, despite the fact that very good safe ERß agonists have been synthesized and at least one has been donated to the NIH for distribution to researchers, who want to study its possible clinical use. Clinical trials are ongoing for the use of ERß agonists in prostate cancer and schizophrenia but even today reviewers of our grants still make comments like "The grant is excellent except that the focus of the grant is ERß". There are multiple reasons for the non-acceptance of the value of ERß and in this paper we will discuss issues raised by labs which do not support a role for ERß in physiology or pathology.

The estrogen receptor variants ß2 and ß5 induce stem cell characteristics and chemotherapy resistance in prostate cancer through activation of hypoxic signaling.

Chemotherapy resistant prostate cancer is a major clinical problem. When the prostate cancer has become androgen deprivation resistant, one of the few treatment regimens left is chemotherapy. There is a strong connection between a cancer's stem cell like characteristics and drug resistance. By performing RNA-seq we observed several factors associated with stem cells being strongly up-regulated by the estrogen receptor ß variants, ß2 and ß5. In addition, most of these factors were also up-regulated by hypoxia. One mechanism of chemotherapy resistance was expression of the hypoxia-regulated, drug transporter genes, where especially ABCG2 and MDR1 were shown to be expressed in recurrent prostate cancer and to cause chemotherapy resistance by efficiently transporting drugs like docetaxel out of the cells. Another mechanism was expression of the hypoxia-regulated Notch3 gene, which causes chemotherapy resistance in urothelial carcinoma, although the mechanism is unknown. It is well known that hypoxic signaling is involved in increasing chemotherapy resistance. Regulation of the hypoxic factors, HIF-1α and HIF-2α is very complex and extends far beyond hypoxia itself. We have recently shown that two of the estrogen receptor ß variants, estrogen receptor ß2 and ß5, bind to and stabilize both HIF-1α and HIF-2α proteins leading to expression of HIF target genes. This study suggests that increased expression of the estrogen receptor ß variants, ß2 and ß5, could be involved in development of a cancer's stem cell characteristics and chemotherapy resistance, indicating that targeting these factors could prevent or reverse chemotherapy resistance and cancer stem cell expansion.

The ERß4 variant induces transformation of the normal breast mammary epithelial cell line MCF-10A; the ERß variants ERß2 and ERß5 increase aggressiveness of TNBC by regulation of hypoxic signaling.

Triple negative breast cancer (TNBC) still remains a challenge to treat in the clinic due to a lack of good targets for treatment. Although TNBC lacks expression of ERα, the expression of ERß and its variants are detected quite frequently in this cancer type and can represent an avenue for treatment. We show that two of the variants of ERß, namely ERß2 and ERß5, control aggressiveness of TNBC by regulating hypoxic signaling through stabilization of HIF-1α. RNA-seq of patient derived xenografts (PDX) from TNBC shows expression of ERß2, ERß4 and ERß5 variants in more than half of the samples. Furthermore, expression of ERß4 in the immortalized, normal mammary epithelial cell line MCF-10A that is resistant to tumorsphere formation caused transformation and development of tumorspheres. By contrast, ERß1, ERß2 or ERß5 were unable to support tumorsphere formation. We have previously shown that all variants except ERß1 stabilize HIF-1α but only ERß4 appears to have the ability to transform normal mammary epithelial cells, pointing towards a unique property of ERß4. We propose that ERß variants may be good diagnostic tools and also serve as novel targets for treatment of breast cancer.

Selective Estrogen Receptor ß Agonist LY500307 as a Novel Therapeutic Agent for Glioblastoma.

Glioblastomas (GBM), deadly brain tumors, have greater incidence in males than females. Epidemiological evidence supports a tumor suppressive role of estrogen; however, estrogen as a potential therapy for GBM is limited due to safety concerns. Since GBM express ERß, a second receptor for estrogen, targeting ERß with a selective agonist may be a potential novel GBM therapy. In the present study, we examined the therapeutic effect of the selective synthetic ERß agonist LY500307 using in vitro and in vivo GBM models. Treatment with LY500307 significantly reduced the proliferation of GBM cells with no activity on normal astrocytes in vitro. ERß agonists promoted apoptosis of GBM cells, and mechanistic studies using RNA sequencing revealed that LY500307 modulated several pathways related to apoptosis, cell cycle, and DNA damage response. Further, LY500307 sensitized GBM cells to several FDA-approved chemotherapeutic drugs including cisplatin, lomustine and temozolomide. LY500307 treatment significantly reduced the in vivo tumor growth and promoted apoptosis of GBM tumors in an orthotopic model and improved the overall survival of tumor-bearing mice in the GL26 syngeneic glioma model. Our results demonstrate that LY500307 has potential as a therapeutic agent for GBM.

BRCA1 inhibits AR-mediated proliferation of breast cancer cells through the activation of SIRT1.

Breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor protein that functions to maintain genomic stability through critical roles in DNA repair, cell-cycle arrest, and transcriptional control. The androgen receptor (AR) is expressed in more than 70% of breast cancers and has been implicated in breast cancer pathogenesis. However, little is known about the role of BRCA1 in AR-mediated cell proliferation in human breast cancer. Here, we report that a high expression of AR in breast cancer patients was associated with shorter overall survival (OS) using a tissue microarray with 149 non-metastatic breast cancer patient samples. We reveal that overexpression of BRCA1 significantly inhibited expression of AR through activation of SIRT1 in breast cancer cells. Meanwhile, SIRT1 induction or treatment with a SIRT1 agonist, resveratrol, inhibits AR-stimulated proliferation. Importantly, this mechanism is manifested in breast cancer patient samples and TCGA database, which showed that low SIRT1 gene expression in tumor tissues compared with normal adjacent tissues predicts poor prognosis in patients with breast cancer. Taken together, our findings suggest that BRCA1 attenuates AR-stimulated proliferation of breast cancer cells via SIRT1 mediated pathway.

The FKBP52 Cochaperone Acts in Synergy with ß-Catenin to Potentiate Androgen Receptor Signaling.

FKBP52 and ß-catenin have emerged in recent years as attractive targets for prostate cancer treatment. ß-catenin interacts directly with the androgen receptor (AR) and has been characterized as a co-activator of AR-mediated transcription. FKBP52 is a positive regulator of AR in cellular and whole animal models and is required for the development of androgen-dependent tissues. We previously characterized an AR inhibitor termed MJC13 that putatively targets the AR BF3 surface to specifically inhibit FKBP52-regulated AR signaling. Predictive modeling suggests that ß-catenin interacts with the AR hormone binding domain on a surface that overlaps with BF3. Here we demonstrate that FKBP52 and ß-catenin interact directly in vitro and act in concert to promote a synergistic up-regulation of both hormone-independent and -dependent AR signaling. Our data demonstrate that FKBP52 promotes ß-catenin interaction with AR and is required for ß-catenin co-activation of AR activity in prostate cancer cells. MJC13 effectively blocks ß-catenin interaction with the AR LBD and the synergistic up-regulation of AR by FKBP52 and ß-catenin. Our data suggest that co-regulation of AR by FKBP52 and ß-catenin does not require FKBP52 PPIase catalytic activity, nor FKBP52 binding to Hsp90. However, the FKBP52 proline-rich loop that overhangs the PPIase pocket is critical for synergy.

Estrogen Receptor ß2 Induces Hypoxia Signature of Gene Expression by Stabilizing HIF-1α in Prostate Cancer.

The estrogen receptor (ER) ß variant ERß2 is expressed in aggressive castration-resistant prostate cancer and has been shown to correlate with decreased overall survival. Genome-wide expression analysis after ERß2 expression in prostate cancer cells revealed that hypoxia was an overrepresented theme. Here we show that ERß2 interacts with and stabilizes HIF-1α protein in normoxia, thereby inducing a hypoxic gene expression signature. HIF-1α is known to stimulate metastasis by increasing expression of Twist1 and increasing vascularization by directly activating VEGF expression. We found that ERß2 interacts with HIF-1α and piggybacks to the HIF-1α response element present on the proximal Twist1 and VEGF promoters. These findings suggest that at least part of the oncogenic effects of ERß2 is mediated by HIF-1α and that targeting of this ERß2 - HIF-1α interaction may be a strategy to treat prostate cancer.

BCL-2 family protein, BAD is down-regulated in breast cancer and inhibits cell invasion.

We have previously demonstrated that the anti-apoptotic protein BAD is expressed in normal human breast tissue and shown that BAD inhibits expression of cyclin D1 to delay cell-cycle progression in breast cancer cells. Herein, expression of proteins in breast tissues was studied by immunohistochemistry and results were analyzed statistically to obtain semi-quantitative data. Biochemical and functional changes in BAD-overexpressing MCF7 breast cancer cells were evaluated using PCR, reporter assays, western blotting, ELISA and extracellular matrix invasion assays. Compared to normal tissues, Grade II breast cancers expressed low total/phosphorylated forms of BAD in both cytoplasmic and nuclear compartments. BAD overexpression decreased the expression of ß-catenin, Sp1, and phosphorylation of STATs. BAD inhibited Ras/MEK/ERK and JNK signaling pathways, without affecting the p38 signaling pathway. Expression of the metastasis-related proteins, MMP10, VEGF, SNAIL, CXCR4, E-cadherin and TlMP2 was regulated by BAD with concomitant inhibition of extracellular matrix invasion. Inhibition of BAD by siRNA increased invasion and Akt/p-Akt levels. Clinical data and the results herein suggest that in addition to the effect on apoptosis, BAD conveys anti-metastatic effects and is a valuable prognostic marker in breast cancer.

A screening cascade to identify ERß ligands.

The establishment of effective high throughput screening cascades to identify nuclear receptor (NR) ligands that will trigger defined, therapeutically useful sets of NR activities is of considerable importance. Repositioning of existing approved drugs with known side effect profiles can provide advantages because de novo drug design suffers from high developmental failure rates and undesirable side effects which have dramatically increased costs. Ligands that target estrogen receptor ß (ERß) could be useful in a variety of diseases ranging from cancer to neurological to cardiovascular disorders. In this context, it is important to minimize cross-reactivity with ERα, which has been shown to trigger increased rates of several types of cancer. Because of high sequence similarities between the ligand binding domains of ERα and ERß, preferentially targeting one subtype can prove challenging. Here, we describe a sequential ligand screening approach comprised of complementary in-house assays to identify small molecules that are selective for ERß. Methods include differential scanning fluorimetry, fluorescence polarization and a GAL4 transactivation assay. We used this strategy to screen several commercially-available chemical libraries, identifying thirty ERß binders that were examined for their selectivity for ERß versus ERα, and tested the effects of selected ligands in a prostate cancer cell proliferation assay. We suggest that this approach could be used to rapidly identify candidates for drug repurposing.

Transcriptional regulation of the sodium-coupled neutral amino acid transporter (SNAT2) by 17ß-estradiol.

The sodium-coupled neutral amino acid transporter 2 (SNAT2) translocates small neutral amino acids into the mammary gland to promote cell proliferation during gestation. It is known that SNAT2 expression increases during pregnancy, and in vitro studies indicate that this transporter is induced by 17ß-estradiol. In this study, we elucidated the mechanism by which 17ß-estradiol regulates the transcription of SNAT2. In silico analysis revealed the presence of a potential estrogen response element (ERE) in the SNAT2 promoter. Reporter assays showed an increase in SNAT2 promoter activity when cotransfected with estrogen receptor alpha (ER-α) after 17ß-estradiol stimulation. Deletion of the ERE reduced estradiol-induced promoter activity by 63%. Additionally, EMSAs and supershift assays showed that ER-α binds to the SNAT2 ERE and that this binding competes with the interaction of ER-α with its consensus ERE. An in vivo ChIP assay demonstrated that the binding of ER-α to the SNAT2 promoter gradually increased in the mammary gland during gestation and that maximal binding occurred at the highest 17ß-estradiol serum concentration. Liquid chromatography-elevated energy mass spectrometry and Western blot analysis revealed that the SNAT2 ER-α-ERE complex contained poly(ADP-ribose) polymerase 1, Lupus Ku autoantigen protein p70, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) proteins and that the silencing of each of these proteins nearly abolished 17ß-estradiol-stimulated SNAT2 promoter activity. Nuclear levels of GAPDH increased progressively during gestation in the mammary gland, and GAPDH binding was nucleotide-specific for the SNAT2 ERE. Thus, this study provides new insights into how the mammary epithelium adapts to control amino acid uptake through the transcriptional regulation of the SNAT2 transporter via 17ß-estradiol.

Insight into the mechanisms of action of estrogen receptor ß in the breast, prostate, colon, and CNS.

Estrogen and its receptors (ERs) influence many biological processes in physiology and pathology in men and women. ERs are involved in the etiology and/or progression of cancers of the prostate, breast, uterus, ovary, colon, lung, stomach, and malignancies of the immune system. In estrogen-sensitive malignancies, ERß usually is a tumor suppressor and ERα is an oncogene. ERß regulates genes in several key pathways including tumor suppression (p53, PTEN); metabolism (PI3K); survival (Akt); proliferation pathways (p45(Skp2), cMyc, and cyclin E); cell-cycle arresting factors (p21(WAF1), cyclin-dependent kinase inhibitor 1 (CDKN1A)), p27(Kip1), and cyclin-dependent kinases (CDKs); protection from reactive oxygen species, glutathione peroxidase. Because they are activated by small molecules, ERs are excellent targets for pharmaceuticals. ERα antagonists have been used for many years in the treatment of breast cancer and more recently pharmaceutical companies have produced agonists which are very selective for ERα or ERß. ERß agonists are being considered for preventing progression of cancer, treatment of anxiety and depression, as anti-inflammatory agents and as agents, which prevent or reduce the severity of neurodegenerative diseases.

Lapatinib induces p27(Kip1)-dependent G1 arrest through both transcriptional and post-translational mechanisms.

Lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor, has been shown to have potent antitumor effects against human breast cancer. Recent studies have shown that lapatinib upregulates p27(Kip1) (here after referred to as p27) expression and induces G1 cell cycle arrest in various types of cancer cells. However, the regulation of p27 in lapatinib-induced cell cycle arrest is not well studied. Here we demonstrate that lapatinib-induced cell growth inhibition and G1 cell cycle arrest in HER2-overexpressing human breast cancer cells were dependent on p27. We also show that lapatinib-induced upregulation of p27 expression was mediated through both transcriptional and post-translational mechanisms. On the one hand, lapatinib treatment led to increased FOXO3a expression and enhanced p27 transcription. On the other hand, lapatinib treatment resulted in increased DYRK1B expression, which correlated with increased p27 phosphorylation at Ser10 and decreased p27 degradation. Interestingly, we found that ERß1 but not ERß2 expression also upregulated p27 and enhanced lapatinib-induced cell proliferation inhibition and G1 cell cycle arrest in HER2-overexpressing breast cancer cells. Taken together, our results suggest that lapatinib induces p27 expression via both transcriptional and post-translational upregulations, leading to cell cycle arrest and cell proliferation inhibition, and that its effect on breast cancer cells may be modified by ER expression status.

Estrogen receptors ß1 and ß2 have opposing roles in regulating proliferation and bone metastasis genes in the prostate cancer cell line PC3.

The estrogen receptor (ER)ß1 is successively lost during cancer progression, whereas its splice variant, ERß2, is expressed in advanced prostate cancer. The latter form of cancer often metastasizes to bone, and we wanted to investigate whether the loss of ERß1 and/or the expression of ERß2 affect such signaling pathways in prostate cancer. Using PC3 and 22Rv1 prostate cancer cell lines that stably express ERß1 or ERß2, we found that the ERß variants differentially regulate genes known to affect tumor behavior. We found that ERß1 repressed the expression of the bone metastasis regulator Runx2 in PC3 cells. By contrast, RUNX2 expression was up-regulated at the mRNA level by ERß2 in PC3 cells, whereas Slug was up-regulated by ERß2 in both PC3 and 22Rv1 cells. In addition, the expression of Twist1, a factor whose expression strongly correlates with high Gleason grade prostate carcinoma, was increased by ERß2. In agreement with the increased Twist1 expression, we found increased expression of Dickkopf homolog 1; Dickkopf homolog 1 is a factor that has been shown to increase the RANK ligand/osteoprotegerin ratio and enhance osteoclastogenesis, indicating that the expression of ERß2 can cause osteolytic cancer. Furthermore, we found that only ERß1 inhibited proliferation, whereas ERß2 increased proliferation. The expression of the proliferation markers Cyclin E, c-Myc, and p45(Skp2) was differentially affected by ERß1 and ERß2 expression. In addition, nuclear ß-catenin protein and its mRNA levels were reduced by ERß1 expression. In conclusion, we found that ERß1 inhibited proliferation and factors known to be involved in bone metastasis, whereas ERß2 increased proliferation and up-regulated factors involved in bone metastasis. Thus, in prostate cancer cells, ERß2 has oncogenic abilities that are in strong contrast to the tumor-suppressing effects of ERß1.

Current concepts and significance of estrogen receptor ß in prostate cancer.

An increasing amount of evidence points at important roles for estrogen receptors in prostate carcinogenesis and progression. Of the two estrogen receptors, estrogen receptor ß is the most prominent within the prostate gland. Although there is much yet to be known, the findings from the discovery of the receptor in 1996 until now point at a role of the receptor in maintaining differentiation and reducing cellular proliferation in the prostate. Moreover, estrogen receptor ß is the main target for phytoestrogens, perhaps at least partially explaining the difference in incidence of prostate cancer in the Western world compared to Asia where the intake of soy-based, phytoestrogen-rich food is higher. The tumor suppressive capability of estrogen receptor ß makes it a promising drug target for the treatment and prevention of prostate cancer. This review will focus on different aspects of estrogen receptor signaling and prostate cancer.