The miR-186-3p/EREG axis orchestrates tamoxifen resistance and aerobic glycolysis in breast cancer cells

He, Mengjia; Jin, Qianni; Chen, Cong; Liu, Yifeng; Ye, Xiangsen; Jiang, Yulin; Ji, Feihu; Qian, Husun; Gan, Delu; Yue, Shujun; Zhu, Wei; Chen, Tingmei

doi:10.1038/s41388-019-0817-3

Cited by 75 publications

(54 citation statements)

References 44 publications

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“…The strong association of CBX2 and glycolysis deregulation with breast cancer aggressiveness suggests the therapeutic potential of targeting oncogenic CBX2 and/or glycolysis. As altered glycolysis has been suggested as a contributor to drug resistance in breast cancer (60)(61)(62)(63) (38) were taken from Molecular Signature Databse (MSigDB) (43) and glycolysis from Recon 1 (37). For patient survival analysis, Kaplan-Meier curves were prepared; P values, hazard ratios (HR) were calculated using the Mantel-Cox and log-rank test respectively, through GraphPad Prism software v7.…”

Section: Discussionmentioning

confidence: 99%

Multiomics integrative analysis reveals antagonistic roles of CBX2 and CBX7 in metabolic reprogramming of breast cancer

Iqbal

Siddiqui

Rehman

et al. 2020

Preprint

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Striking similarity exists between metabolic changes associated with embryogenesis and tumorigenesis. Chromobox proteins-CBX2/4/6/7/8, core components of canonical polycomb repressor complex 1 (cPRC1), play essential roles in embryonic development and aberrantly expressed in breast cancer. Understanding how altered CBX expression relates to metabolic reprogramming in breast cancer may reveal vulnerabilities of therapeutic pertinence. Using transcriptomic and metabolomic data from breast cancer patients (N>3000 combined), we identified outstanding roles of CBX2 and CBX7 in positive and negative regulation of glucose metabolism, respectively. Genetic ablation experiments validated the contrasting roles of two isoforms in cancer metabolism and cell growth. Furthermore, we determined that contrary effects of CBX2 and CBX7 on breast cancer metabolism were due to differential modulation of the mTORC1 signaling by two isoforms. Underpinning the biological significance of metabolic roles, CBX2 and CBX7 were found to be the most up- and down-regulated isoforms, respectively, in breast tumors compared to normal tissues. Moreover, CBX2 and CBX7 expression (not other isoforms) correlated strongly, but oppositely, with breast tumor aggressiveness. Genomic data showed higher amplification frequency of CBX2, not CBX7, in breast tumors. Highlighting the clinical significance of findings, survival and drug sensitivity analysis revealed that CBX2 and CBX7 predicted patient outcome and sensitivity to clinical drugs. In summary, this work identifies previously unknown antagonistic roles of CBX2 and CBX7 in breast tumor metabolism, and the results presented may have implications in strategies targeting breast cancer metabolism.Significance statementMetabolic reprogramming is a hallmark of cancer. Understanding how reprogramming of metabolism is regulated in cancer may reveal therapeutically relevant targets. Using integrative approach, we elucidate the hitherto unknown antagonistic roles of CBX2 and CBX7 in breast cancer metabolism. Highlighting the relevance of identified metabolic roles, we found that CBX2 and CBX7 (not other members) are the most differentially expressed isoforms in breast tumors (compared to normals) and the only isoforms which significantly correlate with breast cancer aggressiveness. Further, CBX2/7 predicted patient outcome and response to drugs used in breast cancer treatment, underscoring clinical significance of our study. In brief, this work unravels novel metabolic roles of CBX2/7 which may have implications in breast cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Multiomics integrative analysis reveals antagonistic roles of CBX2 and CBX7 in metabolic reprogramming of breast cancer

Iqbal

Siddiqui

Rehman

et al. 2020

Preprint

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“…Recently, it was verified that systemic delivery of cholesterol-modified agomiR-186-3p to mice bearing tamoxifen-resistant breast tumors effectively attenuates both tumor growth and 18 F-FDG uptake (Table 1) [104]. Legend: ↑, increase; ↓, decrease; ↔ no effect; -not studied.…”

Section: Mirna-186-3pmentioning

confidence: 99%

Targeting Glucose Transporters for Breast Cancer Therapy: The Effect of Natural and Synthetic Compounds

Barbosa

Martel

2020

Cancers

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Reprogramming of cellular energy metabolism is widely accepted to be a cancer hallmark. The deviant energetic metabolism of cancer cells-known as the Warburg effect-consists in much higher rates of glucose uptake and glycolytic oxidation coupled with the production of lactic acid, even in the presence of oxygen. Consequently, cancer cells have higher glucose needs and thus display a higher sensitivity to glucose deprivation-induced death than normal cells. So, inhibitors of glucose uptake are potential therapeutic targets in cancer. Breast cancer is the most commonly diagnosed cancer and a leading cause of cancer death in women worldwide. Overexpression of facilitative glucose transporters (GLUT), mainly GLUT1, in breast cancer cells is firmly established, and the consequences of GLUT inhibition and/or knockout are under investigation. Herein we review the compounds, both of natural and synthetic origin, found to interfere with uptake of glucose by breast cancer cells, and the consequences of interference with that mechanism on breast cancer cell biology. We will also present data where the interaction with GLUT is exploited in order to increase the efficiency or selectivity of anticancer agents, in breast cancer cells.

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“…Studies by L, X et al [24] indicated that the expression of miR-200b-3p and miR-200c -3p in metastatic CRPC was signi cantly down-regulated, and was negatively correlated with the expression level of PRKAR2B in prostate cancer tissues. At rst, M, H, et al [25]demonstrated that EGFR agonist EREG has played an important role in tamoxifen-resistant breast cancer cells by activating EGFR signaling and its downstream glycolytic genes. It was further proved that EREG was a direct target of miR-186-3p, and tamoxifen downregulation of miR-186-3p could lead to upregulation of EREG in tamoxifen-resistant breast cancer cells [26].…”

Section: Discussionmentioning

confidence: 99%

Development and Validation of A Seven-microRNA Signature as a Novel Prognostic Biomarker for Bladder Cancer

Lin

et al. 2020

Preprint

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Background The differential expression of miRNAs has played a significant role in bladder tumors. The aim of our study was to screen new biomarkers . Methods Through differential analysis of bladder cancer mRNA and miRNA expression data in the TCGA, differential genes and miRNAs were screened. Furthermore, Cox univariate analysis and multifactor analysis were used to establish a prognostic prediction model . The predictive ability of the prognostic model was then verified on the patient. The action mechanism of these miRNAs was analyzed.Results By the differential analysis and standardization of miRNA expression profiles. Differentially expressed miRNAs were screened, then all the patients were then randomly divided into train group and the test group. 23 miRNAs were revealed , then a Seven-miRNA signature prognostic biomarkers was constituting.Univariate cox regression and multivariate cox regression considering other clinical factors displayed that the seven-miRNA signature could serve as an independent prognostic factor.Target genes of these seven miRNAs were analyzed by KEGG signaling pathway and GO enrichment analysis. . Conclusion The prognostic model constructed by seven miRNAs has possessed certain degree of sensitivity and specificity for the prediction of the survival of bladder cancer patients, which can be used as a potential new clinical marker for bladder cancer patients.

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The miR-186-3p/EREG axis orchestrates tamoxifen resistance and aerobic glycolysis in breast cancer cells

Cited by 75 publications

References 44 publications

Multiomics integrative analysis reveals antagonistic roles of CBX2 and CBX7 in metabolic reprogramming of breast cancer

Multiomics integrative analysis reveals antagonistic roles of CBX2 and CBX7 in metabolic reprogramming of breast cancer

Targeting Glucose Transporters for Breast Cancer Therapy: The Effect of Natural and Synthetic Compounds

Development and Validation of A Seven-microRNA Signature as a Novel Prognostic Biomarker for Bladder Cancer

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