Estrogen receptor beta as target for colorectal cancer prevention

Williams, Cecilia; Leo, Alfredo Di; Niv, Yaron; Gustafsson, Jan Åke

doi:10.1016/j.canlet.2015.12.009

Cited by 146 publications

(122 citation statements)

References 96 publications

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“…Similar data have been previously reported for different types of tumors, both related and unrelated to the reproductive system (111–119). …”

Section: Estrogen Receptor β and Melanomasupporting

confidence: 90%

“…These compounds have been suggested as possible effective agents in the prevention of several diseases, such as menopausal symptoms, osteoporosis, and cardiac diseases (145). They have also been reported to exert antitumor activity on different types of cancers, based on their high affinity binding to ERβ and their ability to increase the expression of this receptor subtype (115, 119, 138, 146–148) (Table 1). …”

Section: Natural Erβ Ligands and Melanomamentioning

confidence: 99%

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Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

et al. 2016

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Cutaneous melanoma is an aggressive tumor; its incidence has been reported to increase fast in the past decades. Melanoma is a heterogeneous tumor, with most patients harboring mutations in the BRAF or NRAS oncogenes, leading to the overactivation of the MAPK/ERK and PI3K/Akt pathways. The current therapeutic approaches are based on therapies targeting mutated BRAF and the downstream pathway, and on monoclonal antibodies against the immune checkpoint blockade. However, treatment resistance and side effects are common events of these therapeutic strategies. Increasing evidence supports that melanoma is a hormone-related cancer. Melanoma incidence is higher in males than in females, and females have a significant survival advantage over men. Estrogens exert their effects through estrogen receptors (ERα and ERβ) that affect cancer growth in an opposite way: ERα is associated with a proliferative action and ERβ with an anticancer effect. ERβ is the predominant ER in melanoma, and its expression decreases in melanoma progression, supporting its role as a tumor suppressor. Thus, ERβ is now considered as an effective molecular target for melanoma treatment. 17β-estradiol was reported to inhibit melanoma cells proliferation; however, clinical trials did not provide the expected survival benefits. In vitro studies demonstrate that ERβ ligands inhibit the proliferation of melanoma cells harboring the NRAS (but not the BRAF) mutation, suggesting that ERβ activation might impair melanoma development through the inhibition of the PI3K/Akt pathway. These data suggest that ERβ agonists might be considered as an effective treatment strategy, in combination with MAPK inhibitors, for NRAS mutant melanomas. In an era of personalized medicine, pretreatment evaluation of the expression of ER isoforms together with the concurrent oncogenic mutations should be considered before selecting the most appropriate therapeutic intervention. Natural compounds that specifically bind to ERβ have been identified. These phytoestrogens decrease the proliferation of melanoma cells. Importantly, these effects are unrelated to the oncogenic mutations of melanomas, suggesting that, in addition to their ERβ activating function, these compounds might impair melanoma development through additional mechanisms. A better identification of the role of ERβ in melanoma development will help increase the therapeutic options for this aggressive pathology.

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“…Similar data have been previously reported for different types of tumors, both related and unrelated to the reproductive system (111–119). …”

Section: Estrogen Receptor β and Melanomasupporting

confidence: 90%

Section: Natural Erβ Ligands and Melanomamentioning

confidence: 99%

Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

et al. 2016

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“…Further, estrogen through estrogen receptor β (ERβ/ESR2) appears to reduce the risk of CRC development (reviewed in []). Our previous cell‐based analyses have shown that re‐introduction of ERβ into CRC cells exhibits anti‐proliferative functions, represses oncogenes, and mediates anti‐inflammatory signaling .…”

Section: Introductionmentioning

confidence: 99%

Colitis‐induced colorectal cancer and intestinal epithelial estrogen receptor beta impact gut microbiota diversity

Ibrahim

Hugerth

Hases

et al. 2019

Intl Journal of Cancer

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119

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Chronic inflammation of the colon (colitis) is a risk factor for colorectal cancer (CRC). Hormone‐replacement therapy reduces CRC incidences, and the estrogen receptor beta (ERβ/ESR2) has been implicated in this protection. Gut microbiota is altered in both colitis and CRC and may influence the severity of both. Here we test the hypothesis that intestinal ERβ impacts the gut microbiota. Mice with and without intestine‐specific deletion of ERβ (ERβKO Vil ) were generated using the Cre‐LoxP system. Colitis and CRC were induced with a single intraperitoneal injection of azoxymethane (AOM) followed by administration of three cycles of dextran sulfate sodium (DSS) in drinking water. The microbiota population were characterized by high‐throughput 16S rRNA gene sequencing of DNA extracted from fecal samples ( N = 39). Differences in the microbiota due to AOM/DSS and absence of ERβ were identified through bioinformatic analyses of the 16S‐Seq data, and the distribution of bacterial species was corroborated using qPCR. We demonstrate that colitis‐induced CRC reduced the gut microbiota diversity and that loss of ERβ enhanced this process. Further, the Bacteroidetes genus Prevotellaceae_ UCG_001 was overrepresented in AOM/DSS mice compared to untreated controls (3.5‐fold, p = 0.004), and this was enhanced in females and in ERβKO Vil mice. Overall, AOM/DSS enriched for microbiota impacting immune system diseases and metabolic functions, and lack of ERβ in combination with AOM/DSS enriched for microbiota impacting carbohydrate metabolism and cell motility, while reducing those impacting the endocrine system. Our data support that intestinal ERβ contributes to a more favorable microbiome that could attenuate CRC development.

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“…The loss of expression of ER β is inversely correlated with more advanced Dukes' staging in colon cancer [9]. Cellular experiments supported the tumor suppressive effect of ER β in colon [10]. From the phenotype of ER β −/− mice, there is more colitis-associated neoplasia [11] and ERβ in the colon appears to decrease proliferation and increase apoptosis [12].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic down regulation of G protein-coupled estrogen receptor (GPER) functions as a tumor suppressor in colorectal cancer

et al. 2017

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BackgroundEstrogenic signals are suggested to have protection roles in the development of colorectal cancer (CRC). The G protein-coupled estrogen receptor (GPER) has been reported to mediate non-genomic effects of estrogen in hormone related cancers except CRC. Its expression and functions in CRC were investigated.MethodsThe expression of GPER and its associations with clinicopathological features were examined. The mechanisms were further investigated using cells, mouse xenograft models, and clinical human samples.ResultsGPER was significantly (p < 0.01) down regulated in CRC tissues compared with their matched adjacent normal tissues in our two cohorts and three independent investigations from Oncomine database. Patients whose tumors expressing less (n = 36) GPER showed significant (p < 0.01) poorer survival rate as compared with those with greater levels of GPER (n = 54). Promoter methylation and histone H3 deacetylation were involved in the down regulation of GPER in CRC cell lines and clinical tissues. Activation of GPER by its specific agonist G-1 inhibited proliferation, induced cell cycle arrest, mitochondrial-related apoptosis and endoplasmic reticulum (ER) stress of CRC cells. The upregulation of reactive oxygen species (ROS) induced sustained ERK1/2 activation participated in G-1 induced cell growth arrest. Further, G-1 can inhibit the phosphorylation, nuclear localization, and transcriptional activities of NF-κB via both canonical IKKα/ IκBα pathways and phosphorylation of GSK-3β. Xenograft model based on HCT-116 cells confirmed that G-1 can suppress the in vivo progression of CRC.ConclusionsEpigenetic down regulation of GPER acts as a tumor suppressor in colorectal cancer and its specific activation might be a potential approach for CRC treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0654-3) contains supplementary material, which is available to authorized users.

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Estrogen receptor beta as target for colorectal cancer prevention

Cited by 146 publications

References 96 publications

Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

Colitis‐induced colorectal cancer and intestinal epithelial estrogen receptor beta impact gut microbiota diversity

Epigenetic down regulation of G protein-coupled estrogen receptor (GPER) functions as a tumor suppressor in colorectal cancer

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