Ligand-binding Domain–activating Mutations of ESR1 Rewire Cellular Metabolism of Breast Cancer Cells

Zinger, Lotem; Merenbakh-Lamin, Keren; Klein, Anat; Elazar, Adi; Journo, Shani; Boldes, Tomer; Pasmanik‐Chor, Metsada; Spitzer, Avishay; Rubinek, Tami; Wolf, Ido

doi:10.1158/1078-0432.ccr-18-1505

Cited by 26 publications

(13 citation statements)

References 45 publications

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“…Estrogen and its receptors are essential for sexual development and reproductive function. Previous studies have shown that ESR1 is closely related to the occurrence and development of various urogenital cancers [20][21][22][23], especially breast cancer [24,25] and endometrial cancer [26][27][28]. Recent studies have reported the important role of ESR1 in non-small-cell lung cancer (NSCLC) [29,30] and bladder cancer [31].…”

Section: Discussionmentioning

confidence: 99%

ESR1 as a recurrence-related gene in intrahepatic cholangiocarcinoma: a weighted gene coexpression network analysis

Chen

Yang

et al. 2021

Cancer Cell Int

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Background Intrahepatic cholangiocarcinoma (iCCA) is the second most common malignant hepatic tumor and has a high postoperative recurrence rate and a poor prognosis. The key roles of most tumor recurrence-associated molecules in iCCA remain unclear. This study aimed to explore hub genes related to the postsurgical recurrence of iCCA. Method Differentially expressed genes (DEGs) between iCCA samples and normal liver samples were screened from The Cancer Genome Atlas (TCGA) database and used to construct a weighted gene coexpression network. Module-trait correlations were calculated to identify the key module related to recurrence in iCCA patients. Genes in the key module were subjected to functional enrichment analysis, and candidate hub genes were filtered through coexpression and protein–protein interaction (PPI) network analysis. Validation studies were conducted to detect the “real” hub gene. Furthermore, the biological functions and the underlying mechanism of the real hub gene in iCCA tumorigenesis and progression were determined via in vitro experiments. Results A total of 1019 DEGs were filtered and used to construct four coexpression modules. The red module, which showed the highest correlations with the recurrence status, family history, and day to death of patients, was identified as the key module. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses demonstrated that genes in the red module were enriched in genes and pathways related to tumorigenesis and tumor progression. We performed validation studies and identified estrogen receptor 1 (ESR1), which significantly impacted the prognosis of iCCA patients, as the real hub gene related to the recurrence of iCCA. The in vitro experiments demonstrated that ESR1 overexpression significantly suppressed cell proliferation, migration, and invasion, whereas ESR1 knockdown elicited opposite effects. Further investigation into the mechanism demonstrated that ESR1 acts as a tumor suppressor by inhibiting the JAK/STAT3 signaling pathway. Conclusions ESR1 was identified as the real hub gene related to the recurrence of iCCA that plays a critical tumor suppressor role in iCCA progression. ESR1 significantly impacts the prognosis of iCCA patients and markedly suppresses cholangiocarcinoma cell proliferation, migration and invasion by inhibiting JAK/STAT3 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

ESR1 as a recurrence-related gene in intrahepatic cholangiocarcinoma: a weighted gene coexpression network analysis

Chen

Yang

et al. 2021

Cancer Cell Int

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“…For example, the aggressive nature of ESR1 LBD mutations was attributed to estrogen-independent metabolic rewiring. Compared with breast cancer cells expressing WT ESR1, which are mostly glucose dependent even upon estrogen stimulation, ESR1 Y537S -expressing cells exhibit elevated tricarboxylic acid cycle activity, glucose independence, and reliance on glutamine as an alternative carbon source (Zinger et al, 2019). Sansone et al (2016) performed molecular profiling of pre-and on-treatment tumors from patients in a clinical trial of neoadjuvant letrozole, revealing an inverse correlation between ER and expression of the CSC marker CD133.…”

Section: Epithelial-to-mesenchymal Transitionmentioning

confidence: 99%

Overcoming Endocrine Resistance in Breast Cancer

2020

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Estrogen receptor-positive (ER + ) breast cancer is the most common breast cancer subtype. Treatment of ER + breast cancer comprises interventions that suppress estrogen production and/or target the ER directly (overall labeled as endocrine therapy). While endocrine therapy has considerably reduced recurrence and mortality from breast cancer, de novo and acquired resistance to this treatment remains a major challenge. An increasing number of mechanisms of endocrine resistance have been reported, including somatic alterations, epigenetic changes, and changes in the tumor microenvironment. Here, we review recent advances in delineating mechanisms of resistance to endocrine therapies and potential strategies to overcome such resistance.

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“…Metabolic alteration has wideranging effects, such as angiogenesis, metastasis, and immune escape, which has provided opportunities to solve immunotherapy resistance and poor clinical outcomes (Broadfield et al, 2021;Jones et al, 2021;Zanotelli et al, 2021). To date, the expression patterns of metabolic enzymes have been widely studied in different cancer types, such as liver, gastric, colorectal, breast, and prostate cancer (Lavorgna et al, 2018;Zinger et al, 2019;Rivello et al, 2020;Sun et al, 2020;Xu et al, 2020;Jiang et al, 2021). With the development of nextgeneration sequencing, we can use multiple appropriate statistical methods to analyze TME cell infiltration mediated by metabolic enzymes.…”

Section: Discussionmentioning

confidence: 99%

A Novel Integrated Metabolism-Immunity Gene Expression Model Predicts the Prognosis of Lung Adenocarcinoma Patients

Chen

Duan

et al. 2021

Front. Pharmacol.

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Background: Although multiple metabolic pathways are involved in the initiation, progression, and therapy of lung adenocarcinoma (LUAD), the tumor microenvironment (TME) for immune cell infiltration that is regulated by metabolic enzymes has not yet been characterized.Methods: 517 LUAD samples and 59 non-tumor samples were obtained from The Cancer Genome Atlas (TCGA) database as the training cohort. Kaplan-Meier analysis and Univariate Cox analysis were applied to screen the candidate metabolic enzymes for their role in relation to survival rate in LUAD patients. A prognostic metabolic enzyme signature, termed the metabolic gene risk score (MGRS), was established based on multivariate Cox proportional hazards regression analysis and was verified in an independent test cohort, GSE31210. In addition, we analyzed the immune cell infiltration characteristics in patients grouped by their Risk Score. Furthermore, the prognostic value of these four enzymes was verified in another independent cohort by immunohistochemistry and an optimized model of the metabolic-immune protein risk score (MIPRS) was constructed.Results: The MGRS model comprising 4 genes (TYMS, NME4, LDHA, and SMOX) was developed to classify patients into high-risk and low-risk groups. Patients with a high-risk score had a poor prognosis and exhibited activated carbon and nucleotide metabolism, both of which were associated with changes to TME immune cell infiltration characteristics. In addition, the optimized MIPRS model showed more accurate predictive power in prognosis of LUAD.Conclusion: Our study revealed an integrated metabolic enzyme signature as a reliable prognostic tool to accurately predict the prognosis of LUAD.

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Ligand-binding Domain–activating Mutations of ESR1 Rewire Cellular Metabolism of Breast Cancer Cells

Cited by 26 publications

References 45 publications

ESR1 as a recurrence-related gene in intrahepatic cholangiocarcinoma: a weighted gene coexpression network analysis

ESR1 as a recurrence-related gene in intrahepatic cholangiocarcinoma: a weighted gene coexpression network analysis

Overcoming Endocrine Resistance in Breast Cancer

A Novel Integrated Metabolism-Immunity Gene Expression Model Predicts the Prognosis of Lung Adenocarcinoma Patients

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