Expression of G protein‐coupled oestrogen receptor in melanoma and in pregnancy‐associated melanoma

Fábián, Melinda; Rencz, Fanni; Krenács, Tibor; Brodszky, Valentin; Hársing, Judit; Németh, Krisztián; Balogh, Petra; Kárpáti, Sarolta

doi:10.1111/jdv.14304

Cited by 18 publications

(16 citation statements)

References 73 publications

(169 reference statements)

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“…Here, we demonstrate that this nonclassical estrogen signaling promotes differentiation in melanoma, inhibits tumor cell proliferation, and critically, promotes a phenotype that renders tumors more susceptible to immune-mediated elimination ( Figure 7 ). Consistent with this, recent independent work from others has demonstrated that GPER protein levels are higher in human pregnancy-associated melanoma compared to melanoma from non-pregnant females or men, and that high GPER expression is associated with favorable prognostic indicators including decreased Breslow depth, decreased mitotic rate, and increased lymphocyte infiltration into tumor ( Fábián et al, 2017 ). Conclusions from our current study are consistent with those clinical observations.…”

Section: Discussionmentioning

confidence: 65%

“…Together, these data indicate that GPER activation regulates c-Myc through protein degradation. A recent report showed that melanomas arising during pregnancy are associated with higher GPER protein within tumor sections, suggesting that hormonal factors may upregulate GPER expression ( Fábián et al, 2017 ). Consistent with these clinical data, G-1 induced a dose-dependent increase in GPER expression in melanoma cells ( Figure 3—figure supplement 1A ).…”

Section: Resultsmentioning

confidence: 99%

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Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade

Natale

Zhang

et al. 2018

eLife

106

111

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Female sex and history of prior pregnancies are associated with favorable melanoma outcomes. Here, we show that much of the melanoma protective effect likely results from estrogen signaling through the G protein-coupled estrogen receptor (GPER) on melanocytes. Selective GPER activation in primary melanocytes and melanoma cells induced long-term changes that maintained a more differentiated cell state as defined by increased expression of well-established melanocyte differentiation antigens, increased pigment production, decreased proliferative capacity, and decreased expression of the oncodriver and stem cell marker c-Myc. GPER signaling also rendered melanoma cells more vulnerable to immunotherapy. Systemically delivered GPER agonist was well tolerated, and cooperated with immune checkpoint blockade in melanoma-bearing mice to dramatically extend survival, with up to half of mice clearing their tumor. Complete responses were associated with immune memory that protected against tumor rechallenge. GPER may be a useful, pharmacologically accessible target for melanoma.

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Section: Discussionmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade

Natale

Zhang

et al. 2018

eLife

106

111

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“…Concerning in vitro studies, several melanoma cell lines express ERβ, irrespective of genetic background [24]. GPER is also expressed in melanoma [25] its co-expression with ERβ being associated with better outcomes, especially in pregnancy-associated melanoma [26]. The nuclear receptor superfamily also includes the androgen receptor (AR), consisting of α and β isoforms encoded by a gene located on the X chromosome [27].…”

Section: Sex Steroid Hormone Receptors In Melanomamentioning

confidence: 99%

Sex and Gender Disparities in Melanoma

Bellenghi

Puglisi

Pontecorvi

et al. 2020

Cancers

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Worldwide, the total incidence of cutaneous melanoma is higher in men than in women, with some differences related to ethnicity and age and, above all, sex and gender. Differences exist in respect to the anatomic localization of melanoma, in that it is more frequent on the trunk in men and on the lower limbs in women. A debated issue is if—and to what extent—melanoma development can be attributed to gender-specific behaviors or to biologically intrinsic differences. In the search for factors responsible for the divergences, a pivotal role of sex hormones has been observed, although conflicting results indicate the involvement of other mechanisms. The presence on the X chromosome of numerous miRNAs and coding genes playing immunological roles represents another important factor, whose relevance can be even increased by the incomplete X chromosome random inactivation. Considering the known advantages of the female immune system, a different cancer immune surveillance efficacy was suggested to explain some sex disparities. Indeed, the complexity of this picture emerged when the recently developed immunotherapies unexpectedly showed better improvements in men than in women. Altogether, these data support the necessity of further studies, which consider enrolling a balanced number of men and women in clinical trials to better understand the differences and obtain actual gender-equitable healthcare.

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“…Also, Eleftherios et al [38] reported that the expression of cytoplasmic GPER was significantly associated with increased histologic tumor differentiation (low grade), and favorable OS in patients with primary invasive breast carcinomas. Fabian et al [19] reported that the presence of GPER predicted a better DFS in patients with melanoma. Heublein et al [39] found that GPER activation reduced the proliferation rate of ovarian cancer cells, and increased expression of GPER was associated with an increased OS.…”

Section: Discussionmentioning

confidence: 99%

“…Cui et al [15] showed that upregulation of the expression of GPER in papillary thyroid carcinoma and high levels of GPER protein were correlated with lymph node metastasis. However, studies have shown that GPER might act as a tumor suppressor in several types of human cancer, including non-small cell lung cancer (NSCLC) [16], hepatocellular carcinoma (HCC) [17], triple-negative breast cancer (TNBC) [18], melanoma [19], prostate cancer [20] and cervical cancer [21]. However, the association between GPER expression and clinical outcome in patients with gastric cancer remains to be investigated.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of G Protein-Coupled Estrogen Receptor (GPER) is Associated with Reduced Prognosis in Patients with Gastric Cancer

Tian

Zhan

et al. 2019

Med Sci Monit

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Background This study is aimed to investigate the prognostic significance of the expression of G protein-coupled estrogen receptor (GPER) in gastric cancer tissue using bioinformatics data and immunohistochemistry. Material/Methods Expression of GPER mRNA in gastric cancer tissues and normal adjacent tissues was investigated using data from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and Oncomine database. Kaplan-Meier Plotter identified the association between GPER mRNA and prognosis. Correlation between GPER mRNA and DNA methylation used the cBioPortal for Cancer Genomics and the MethHC website. Genes co-expressed with GPER were identified from The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) underwent FunRich analysis. Immunohistochemistry and Western blot evaluated GPER protein expression in tissue microarrays (TMAs) and gastric cancer cell lines. Results GPER mRNA and protein levels were significantly lower in gastric cancer tissue and cells lined when compared with normal tissues and cells. The results from GSE15459 showed that patients with low levels of GPER mRNA had a reduced overall survival (OS) (P=0.013) and disease-free survival (DFS) (P=0.019). A negative correlation (r=−0.611) between GPER mRNA and DNA methylation was found using the cBioPortal and MethHC. Co-expressed epithelial-mesenchymal transformation (EMT) genes were enriched with GPER (P<0.0001). Cox regression analysis showed that GPER protein expression was an independent prognostic factor (P=0.035) Conclusions Downregulation of GPER predicts poor prognosis in gastric cancer. GPER may act as a tumor suppressor through the regulation of EMT in gastric cancer.

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Expression of G protein‐coupled oestrogen receptor in melanoma and in pregnancy‐associated melanoma

Abstract: The presence of GPER and its simultaneous expression with ERβ can serve as a new prognostic indicator in a significant subpopulation of melanoma patients.

Cited by 18 publications

References 73 publications

Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade

Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade

Sex and Gender Disparities in Melanoma

Downregulation of G Protein-Coupled Estrogen Receptor (GPER) is Associated with Reduced Prognosis in Patients with Gastric Cancer

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