Cholesterol-Induced Metabolic Reprogramming in Breast Cancer Cells Is Mediated via the ERRα Pathway
The molecular mechanism underlying the metabolic reprogramming associated with obesity and high blood cholesterol levels is poorly understood. We previously reported that cholesterol is an endogenous ligand of the estrogen-related receptor alpha (ERRα). Using functional assays, metabolomics, and gen...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/11/2605 |
| _version_ | 1797532593805066240 |
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| author | Faegheh Ghanbari Anne-Marie Fortier Morag Park Anie Philip |
| author_facet | Faegheh Ghanbari Anne-Marie Fortier Morag Park Anie Philip |
| author_sort | Faegheh Ghanbari |
| collection | DOAJ |
| description | The molecular mechanism underlying the metabolic reprogramming associated with obesity and high blood cholesterol levels is poorly understood. We previously reported that cholesterol is an endogenous ligand of the estrogen-related receptor alpha (ERRα). Using functional assays, metabolomics, and genomics, here we show that exogenous cholesterol alters the metabolic pathways in estrogen receptor-positive (ER+) and triple-negative breast cancer (TNBC) cells, and that this involves increased oxidative phosphorylation (OXPHOS) and TCA cycle intermediate levels. In addition, cholesterol augments aerobic glycolysis in TNBC cells although it remains unaltered in ER+ cells. Interestingly, cholesterol does not alter the metabolite levels of glutaminolysis, one-carbon metabolism, or the pentose phosphate pathway, but increases the NADPH levels and cellular proliferation, in both cell types. Importantly, we show that the above cholesterol-induced modulations of the metabolic pathways in breast cancer cells are mediated via ERRα. Furthermore, analysis of the ERRα metabolic gene signature of basal-like breast tumours of overweight/obese versus lean patients, using the GEO database, shows that obesity may modulate ERRα gene signature in a manner consistent with our in vitro findings with exogenous cholesterol. Given the close link between high cholesterol levels and obesity, our findings provide a mechanistic explanation for the association between cholesterol/obesity and metabolic reprogramming in breast cancer patients. |
| first_indexed | 2024-03-10T11:02:26Z |
| format | Article |
| id | doaj.art-6a0c0236b22e4cf9a0f655dd9b6c079c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T11:02:26Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-6a0c0236b22e4cf9a0f655dd9b6c079c2023-11-21T21:25:58ZengMDPI AGCancers2072-66942021-05-011311260510.3390/cancers13112605Cholesterol-Induced Metabolic Reprogramming in Breast Cancer Cells Is Mediated via the ERRα PathwayFaegheh Ghanbari0Anne-Marie Fortier1Morag Park2Anie Philip3Division of Plastic Surgery, Department of Surgery, Faculty of Medicine, McGill University, Montreal, QC H3G 1A4, CanadaGoodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, CanadaGoodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, CanadaDivision of Plastic Surgery, Department of Surgery, Faculty of Medicine, McGill University, Montreal, QC H3G 1A4, CanadaThe molecular mechanism underlying the metabolic reprogramming associated with obesity and high blood cholesterol levels is poorly understood. We previously reported that cholesterol is an endogenous ligand of the estrogen-related receptor alpha (ERRα). Using functional assays, metabolomics, and genomics, here we show that exogenous cholesterol alters the metabolic pathways in estrogen receptor-positive (ER+) and triple-negative breast cancer (TNBC) cells, and that this involves increased oxidative phosphorylation (OXPHOS) and TCA cycle intermediate levels. In addition, cholesterol augments aerobic glycolysis in TNBC cells although it remains unaltered in ER+ cells. Interestingly, cholesterol does not alter the metabolite levels of glutaminolysis, one-carbon metabolism, or the pentose phosphate pathway, but increases the NADPH levels and cellular proliferation, in both cell types. Importantly, we show that the above cholesterol-induced modulations of the metabolic pathways in breast cancer cells are mediated via ERRα. Furthermore, analysis of the ERRα metabolic gene signature of basal-like breast tumours of overweight/obese versus lean patients, using the GEO database, shows that obesity may modulate ERRα gene signature in a manner consistent with our in vitro findings with exogenous cholesterol. Given the close link between high cholesterol levels and obesity, our findings provide a mechanistic explanation for the association between cholesterol/obesity and metabolic reprogramming in breast cancer patients.https://www.mdpi.com/2072-6694/13/11/2605n/a |
| spellingShingle | Faegheh Ghanbari Anne-Marie Fortier Morag Park Anie Philip Cholesterol-Induced Metabolic Reprogramming in Breast Cancer Cells Is Mediated via the ERRα Pathway Cancers n/a |
| title | Cholesterol-Induced Metabolic Reprogramming in Breast Cancer Cells Is Mediated via the ERRα Pathway |
| title_full | Cholesterol-Induced Metabolic Reprogramming in Breast Cancer Cells Is Mediated via the ERRα Pathway |
| title_fullStr | Cholesterol-Induced Metabolic Reprogramming in Breast Cancer Cells Is Mediated via the ERRα Pathway |
| title_full_unstemmed | Cholesterol-Induced Metabolic Reprogramming in Breast Cancer Cells Is Mediated via the ERRα Pathway |
| title_short | Cholesterol-Induced Metabolic Reprogramming in Breast Cancer Cells Is Mediated via the ERRα Pathway |
| title_sort | cholesterol induced metabolic reprogramming in breast cancer cells is mediated via the errα pathway |
| topic | n/a |
| url | https://www.mdpi.com/2072-6694/13/11/2605 |
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