Metabolomic Profiling Reveals Key Metabolic Alterations in MCF7 Tamoxifen-Resistant Cells Following EPAS1 Inhibition
Tamoxifen (TAM) is a frontline therapy for luminal A breast cancer, yet acquired resistance poses a significant clinical challenge. This study investigates the molecular and metabolic basis of TAM resistance in MCF7/Tam1 cells, focusing on EPAS1 (HIF-2α)-driven hypoxia-induced metabolic reprogrammin...
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2025
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| _version_ | 1851484483444801536 |
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| author | Enzhi Luo (21737638) |
| author2 | Neeraj Manvi Agarwal (21737641) Junjeong Choi (795304) |
| author2_role | author author |
| author_facet | Enzhi Luo (21737638) Neeraj Manvi Agarwal (21737641) Junjeong Choi (795304) |
| author_role | author |
| dc.creator.none.fl_str_mv | Enzhi Luo (21737638) Neeraj Manvi Agarwal (21737641) Junjeong Choi (795304) |
| dc.date.none.fl_str_mv | 2025-07-18T01:29:48Z |
| dc.identifier.none.fl_str_mv | 10.1021/acs.jproteome.5c00170.s002 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/dataset/Metabolomic_Profiling_Reveals_Key_Metabolic_Alterations_in_MCF7_Tamoxifen-Resistant_Cells_Following_EPAS1_Inhibition/29595001 |
| dc.rights.none.fl_str_mv | CC BY-NC 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biochemistry Microbiology Cell Biology Genetics Physiology Pharmacology Biotechnology Cancer Hematology Computational Biology Chemical Sciences not elsewhere classified significant clinical challenge promising therapeutic strategy fatty acid oxidation mediated metabolic reprogramming induced metabolic reprogramming support epas1 inhibition findings highlight epas1 enhanced glutamine metabolism restore tam sensitivity epas1 inhibitor pt2977 metabolic pathways metabolic basis epas1 along lipid metabolism glutathione metabolism warburg effect venn analyses untargeted lc tam1 cells tam stress tam resistance study investigates selective reduction resistant cells redox balance pt2977 disrupted overcome resistance notable dysregulation metabolite profiles key driver including jak frontline therapy dependent normalization cell viability cell survival breast cancer associated pathways |
| dc.title.none.fl_str_mv | Metabolomic Profiling Reveals Key Metabolic Alterations in MCF7 Tamoxifen-Resistant Cells Following EPAS1 Inhibition |
| dc.type.none.fl_str_mv | Dataset info:eu-repo/semantics/publishedVersion dataset |
| description | Tamoxifen (TAM) is a frontline therapy for luminal A breast cancer, yet acquired resistance poses a significant clinical challenge. This study investigates the molecular and metabolic basis of TAM resistance in MCF7/Tam1 cells, focusing on EPAS1 (HIF-2α)-driven hypoxia-induced metabolic reprogramming and the potential of the EPAS1 inhibitor PT2977 to restore TAM sensitivity. Comparative transcriptomic analysis revealed upregulation of EPAS1 along with enrichment of hypoxia-associated pathways, including JAK-STAT, TGF-beta, and lipid metabolism in resistant cells. Untargeted LC-MS/MS metabolomics identified 1,039 significantly altered metabolites, with notable dysregulation in glutamate and glutathione metabolism, the Warburg effect, and fatty acid oxidation. Mechanistically, EPAS1 promoted fatty acid uptake via CD36 and enhanced glutamine metabolism through SLC1A5, contributing to redox balance and cell survival under TAM stress. Treatment with PT2977 disrupted these metabolic pathways, as evidenced by PCA and Venn analyses, leading to a dose-dependent normalization of metabolite profiles and selective reduction in cell viability. These findings highlight EPAS1-mediated metabolic reprogramming as a key driver of TAM resistance and support EPAS1 inhibition by PT2977 as a promising therapeutic strategy to overcome resistance in luminal A breast cancer. |
| eu_rights_str_mv | openAccess |
| id | Manara_c99ce248e566f996ea8bce3e906a4ea5 |
| identifier_str_mv | 10.1021/acs.jproteome.5c00170.s002 |
| network_acronym_str | Manara |
| network_name_str | ManaraRepo |
| oai_identifier_str | oai:figshare.com:article/29595001 |
| publishDate | 2025 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY-NC 4.0 |
| spelling | Metabolomic Profiling Reveals Key Metabolic Alterations in MCF7 Tamoxifen-Resistant Cells Following EPAS1 InhibitionEnzhi Luo (21737638)Neeraj Manvi Agarwal (21737641)Junjeong Choi (795304)BiochemistryMicrobiologyCell BiologyGeneticsPhysiologyPharmacologyBiotechnologyCancerHematologyComputational BiologyChemical Sciences not elsewhere classifiedsignificant clinical challengepromising therapeutic strategyfatty acid oxidationmediated metabolic reprogramminginduced metabolic reprogrammingsupport epas1 inhibitionfindings highlight epas1enhanced glutamine metabolismrestore tam sensitivityepas1 inhibitor pt2977metabolic pathwaysmetabolic basisepas1 alonglipid metabolismglutathione metabolismwarburg effectvenn analysesuntargeted lctam1 cellstam stresstam resistancestudy investigatesselective reductionresistant cellsredox balancept2977 disruptedovercome resistancenotable dysregulationmetabolite profileskey driverincluding jakfrontline therapydependent normalizationcell viabilitycell survivalbreast cancerassociated pathwaysTamoxifen (TAM) is a frontline therapy for luminal A breast cancer, yet acquired resistance poses a significant clinical challenge. This study investigates the molecular and metabolic basis of TAM resistance in MCF7/Tam1 cells, focusing on EPAS1 (HIF-2α)-driven hypoxia-induced metabolic reprogramming and the potential of the EPAS1 inhibitor PT2977 to restore TAM sensitivity. Comparative transcriptomic analysis revealed upregulation of EPAS1 along with enrichment of hypoxia-associated pathways, including JAK-STAT, TGF-beta, and lipid metabolism in resistant cells. Untargeted LC-MS/MS metabolomics identified 1,039 significantly altered metabolites, with notable dysregulation in glutamate and glutathione metabolism, the Warburg effect, and fatty acid oxidation. Mechanistically, EPAS1 promoted fatty acid uptake via CD36 and enhanced glutamine metabolism through SLC1A5, contributing to redox balance and cell survival under TAM stress. Treatment with PT2977 disrupted these metabolic pathways, as evidenced by PCA and Venn analyses, leading to a dose-dependent normalization of metabolite profiles and selective reduction in cell viability. These findings highlight EPAS1-mediated metabolic reprogramming as a key driver of TAM resistance and support EPAS1 inhibition by PT2977 as a promising therapeutic strategy to overcome resistance in luminal A breast cancer.2025-07-18T01:29:48ZDatasetinfo:eu-repo/semantics/publishedVersiondataset10.1021/acs.jproteome.5c00170.s002https://figshare.com/articles/dataset/Metabolomic_Profiling_Reveals_Key_Metabolic_Alterations_in_MCF7_Tamoxifen-Resistant_Cells_Following_EPAS1_Inhibition/29595001CC BY-NC 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/295950012025-07-18T01:29:48Z |
| spellingShingle | Metabolomic Profiling Reveals Key Metabolic Alterations in MCF7 Tamoxifen-Resistant Cells Following EPAS1 Inhibition Enzhi Luo (21737638) Biochemistry Microbiology Cell Biology Genetics Physiology Pharmacology Biotechnology Cancer Hematology Computational Biology Chemical Sciences not elsewhere classified significant clinical challenge promising therapeutic strategy fatty acid oxidation mediated metabolic reprogramming induced metabolic reprogramming support epas1 inhibition findings highlight epas1 enhanced glutamine metabolism restore tam sensitivity epas1 inhibitor pt2977 metabolic pathways metabolic basis epas1 along lipid metabolism glutathione metabolism warburg effect venn analyses untargeted lc tam1 cells tam stress tam resistance study investigates selective reduction resistant cells redox balance pt2977 disrupted overcome resistance notable dysregulation metabolite profiles key driver including jak frontline therapy dependent normalization cell viability cell survival breast cancer associated pathways |
| status_str | publishedVersion |
| title | Metabolomic Profiling Reveals Key Metabolic Alterations in MCF7 Tamoxifen-Resistant Cells Following EPAS1 Inhibition |
| title_full | Metabolomic Profiling Reveals Key Metabolic Alterations in MCF7 Tamoxifen-Resistant Cells Following EPAS1 Inhibition |
| title_fullStr | Metabolomic Profiling Reveals Key Metabolic Alterations in MCF7 Tamoxifen-Resistant Cells Following EPAS1 Inhibition |
| title_full_unstemmed | Metabolomic Profiling Reveals Key Metabolic Alterations in MCF7 Tamoxifen-Resistant Cells Following EPAS1 Inhibition |
| title_short | Metabolomic Profiling Reveals Key Metabolic Alterations in MCF7 Tamoxifen-Resistant Cells Following EPAS1 Inhibition |
| title_sort | Metabolomic Profiling Reveals Key Metabolic Alterations in MCF7 Tamoxifen-Resistant Cells Following EPAS1 Inhibition |
| topic | Biochemistry Microbiology Cell Biology Genetics Physiology Pharmacology Biotechnology Cancer Hematology Computational Biology Chemical Sciences not elsewhere classified significant clinical challenge promising therapeutic strategy fatty acid oxidation mediated metabolic reprogramming induced metabolic reprogramming support epas1 inhibition findings highlight epas1 enhanced glutamine metabolism restore tam sensitivity epas1 inhibitor pt2977 metabolic pathways metabolic basis epas1 along lipid metabolism glutathione metabolism warburg effect venn analyses untargeted lc tam1 cells tam stress tam resistance study investigates selective reduction resistant cells redox balance pt2977 disrupted overcome resistance notable dysregulation metabolite profiles key driver including jak frontline therapy dependent normalization cell viability cell survival breast cancer associated pathways |