Crosstalk of estrogen receptors and Wnt/β-catenin signaling in endometrial cancer

Kasoha, Mariz; Dernektsi, Chrisoula; Seibold, Anita; Bohle, Rainer M.; Takács, Zoltán; Iordache, Ioan-Iulian; Solomayer, Erich‐Franz; Juhasz‐Böss, I.

doi:10.1007/s00432-019-03114-8

Cited by 20 publications

(19 citation statements)

References 36 publications

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“…Based on the results of the miRNome analysis with the use of the next-generation sequencing method and subsequent bioinformatic analysis with the MirWalk and MirTarBase programs [ 26 ], we hypothesized that genes encoding estrogen receptors are possible targets of miRNAs that are differentially expressed in the investigated tissues. Upon the in silico analysis, as well as based on the previously published data reporting the results of functional studies performed on human biological material, we selected hsa-miR-18a-5p, hsa-miR-18b-5p, hsa-miR-22-3p, hsa-miR-100-5p, hsa-miR-142-3p, and hsa-miR-143-5p for the analysis of ESR1 , and hsa-miR-146b-3p, hsa-miR-20b-5p, hsa-miR-335-3p, hsa-miR-495-3p, and hsa-miR-576-5p for the analysis of ESR2 [ 21 , 22 , 27 , 28 , 29 , 30 ]. We previously found that all these miRNAs have significantly different expression levels between adipose tissues obtained from obese and normal-weight individuals [ 26 ].…”

Section: Resultsmentioning

confidence: 99%

Epigenetic Regulation of Estrogen Receptor Genes’ Expressions in Adipose Tissue in the Course of Obesity

Koźniewski

Wąsowski

Jonas

et al. 2022

IJMS

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Estrogen affects adipose tissue function. Therefore, this study aimed at assessing changes in the transcriptional activity of estrogen receptor (ER) α and β genes (ESR1 and ESR2, respectively) in the adipose tissues of obese individuals before and after weight loss and verifying whether epigenetic mechanisms were involved in this phenomenon. ESR1 and ESR2 mRNA and miRNA levels were evaluated using real-time PCR in visceral (VAT) and subcutaneous adipose tissue (SAT) of 78 obese (BMI > 40 kg/m2) and 31 normal-weight (BMI = 20–24.9 kg/m2) individuals and in 19 SAT samples from post-bariatric patients. ESR1 and ESR2 methylation status was studied using the methylation-sensitive digestion/real-time PCR method. Obesity was associated with a decrease in mRNA levels of both ERs in SAT (p < 0.0001) and ESR2 in VAT (p = 0.0001), while weight loss increased ESR transcription (p < 0.0001). Methylation levels of ESR1 and ESR2 promoters were unaffected. However, ESR1 mRNA in the AT of obese subjects correlated negatively with the expression of hsa-miR-18a-5p (rs = −0.444), hsa-miR-18b-5p (rs = −0.329), hsa-miR-22-3p (rs = −0.413), hsa-miR-100-5p (rs = −0.371), and hsa-miR-143-5p (rs = −0.289), while the expression of ESR2 in VAT correlated negatively with hsa-miR-576-5p (rs=-0.353) and in SAT with hsa-miR-495-3p (rs = −0.308). In conclusion, obesity-associated downregulation of ER mRNA levels in adipose tissue may result from miRNA interference.

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Section: Resultsmentioning

confidence: 99%

Epigenetic Regulation of Estrogen Receptor Genes’ Expressions in Adipose Tissue in the Course of Obesity

Koźniewski

Wąsowski

Jonas

et al. 2022

IJMS

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“…Proteins of our screening assay cover a wide range of functions, which are revealed by literature research to be related to the estrogen-dependent signaling pathway, such as cell growth (amphiregulin, EGFR) [ 72 , 73 , 74 ], apoptosis (p53, Bcl-XL, survivin) [ 75 , 76 ], metastasis development (Dkk1, galectin 3, EpCAM, cathepsins) [ 77 , 78 , 79 , 80 ], and tumor immunoregulation (IL6, IL8, CCL20) [ 81 , 82 , 83 , 84 ]. An interesting yet conflicting phenomenon was observed during the summary of the protein expression experiments.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the Antitumor Effects of Tamoxifen and Its Ferrocene-Linked Derivatives on Pancreatic and Breast Cancer Cell Lines

et al. 2022

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Tamoxifen is a long-known anti-tumor drug, which is the gold standard therapy in estrogen receptor (ER) positive breast cancer patients. According to previous studies, the conjugation of the original tamoxifen molecule with different functional groups can significantly improve its antitumor effect. The purpose of this research was to uncover the molecular mechanisms behind the cytotoxicity of different ferrocene-linked tamoxifen derivates. Tamoxifen and its ferrocene-linked derivatives, T5 and T15 were tested in PANC1, MCF7, and MDA-MB-231 cells, where the incorporation of the ferrocene group improved the cytotoxicity on all cell lines. PANC1, MCF7, and MDA-MB-231 express ERα and GPER1 (G-protein coupled ER 1). However, ERβ is only expressed by MCF7 and MDA-MB-231 cells. Tamoxifen is a known agonist of GPER1, a receptor that can promote tumor progression. Analysis of the protein expression profile showed that while being cytotoxic, tamoxifen elevated the levels of different tumor growth-promoting factors (e.g., Bcl-XL, Survivin, EGFR, Cathepsins, chemokines). On the other hand, the ferrocene-linked derivates were able to lower these proteins. Further analysis showed that the ferrocene-linked derivatives significantly elevated the cellular oxidative stress compared to tamoxifen treatment. In conclusion, we were able to find two molecules possessing better cytotoxicity compared to their unmodified parent molecule while also being able to counter the negative effects of the presence of the GPER1 through the ER-independent mechanism of oxidative stress induction.

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“… Gupta et al, (2011) demonstrated that ß-catenin is a positive regulator of ERα function in breast cancer cells ( Gupta et al, 2011 ). Moreover, the protein level of ERα is correlated with DKK1, a target gene of Wnt/ß-catenin signaling, highlighting the crosstalk between ERα and ß-catenin signaling in endometrial cancer ( Kasoha et al, 2019 ). Generally, naringenin’s effect on the Wnt/ß-catenin pathway, p53, and ERα in inhibiting BCSCs is highlighted as an interesting topic for future research.…”

Section: Discussionmentioning

confidence: 99%

Identification of potential therapeutic target of naringenin in breast cancer stem cells inhibition by bioinformatics and in vitro studies

Hermawan

Ikawati

Jenie

et al. 2021

Saudi Pharmaceutical Journal

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Cancer therapy is a strategic measure in inhibiting breast cancer stem cell (BCSC) pathways. Naringenin, a citrus flavonoid, was found to increase breast cancer cells’ sensitivity to chemotherapeutic agents. Bioinformatics study and 3D tumorsphere in vitro modeling in breast cancer (mammosphere) were used in this study, which aims to explore the potential therapeutic targets of naringenin (PTTNs) in inhibiting BCSCs. Bioinformatic analyses identified direct target proteins (DTPs), indirect target proteins (ITPs), naringenin-mediated proteins (NMPs), BCSC regulatory genes, and PTTNs. The PTTNs were further analyzed for gene ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, protein–protein interaction (PPI) networks, and hub protein selection. Mammospheres were cultured in serum-free media. The effects of naringenin were measured by MTT-based cytotoxicity, mammosphere forming potential (MFP), colony formation, scratch wound-healing assay, and flow cytometry-based cell cycle analyses and apoptosis assays. Gene expression analysis was performed using real-time quantitative polymerase chain reaction (q-RT PCR). Bioinformatics analysis revealed p53 and estrogen receptor alpha (ERα) as PTTNs, and KEGG pathway enrichment analysis revealed that TGF-ß and Wnt/ß-catenin pathways are regulated by PTTNs. Naringenin demonstrated cytotoxicity and inhibited mammosphere and colony formation, migration, and epithelial to mesenchymal transition in the mammosphere. The mRNA of tumor suppressors P53 and ERα were downregulated in the mammosphere, but were significantly upregulated upon naringenin treatment. By modulating the P53 and ERα mRNA, naringenin has the potential of inhibiting BCSCs. Further studies on the molecular mechanism and formulation of naringenin in BCSCs would be beneficial for its development as a BCSC-targeting drug.

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Crosstalk of estrogen receptors and Wnt/β-catenin signaling in endometrial cancer

Cited by 20 publications

References 36 publications

Epigenetic Regulation of Estrogen Receptor Genes’ Expressions in Adipose Tissue in the Course of Obesity

Epigenetic Regulation of Estrogen Receptor Genes’ Expressions in Adipose Tissue in the Course of Obesity

Investigation of the Antitumor Effects of Tamoxifen and Its Ferrocene-Linked Derivatives on Pancreatic and Breast Cancer Cell Lines

Identification of potential therapeutic target of naringenin in breast cancer stem cells inhibition by bioinformatics and in vitro studies

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