Hypoxia-Driven TGFβ Modulation of Side Population Cells in Breast Cancer: The Potential Role of ERα
Epithelial-to-mesenchymal transition (EMT) is known to be important in regulating the behaviour of cancer cells enabling them to acquire stem cell characteristics or by enhancing the stem cell characteristics of cancer stem cells, resulting in these cells becoming more migratory and invasive. EMT ca...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/4/1108 |
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| author | Paraskevi Mallini Miaojuan Chen Kamilla Mahkamova Thomas W. J. Lennard Yue Pan Dan Wei Katherine Stemke-Hale John A. Kirby Gendie E. Lash Annette Meeson |
| author_facet | Paraskevi Mallini Miaojuan Chen Kamilla Mahkamova Thomas W. J. Lennard Yue Pan Dan Wei Katherine Stemke-Hale John A. Kirby Gendie E. Lash Annette Meeson |
| author_sort | Paraskevi Mallini |
| collection | DOAJ |
| description | Epithelial-to-mesenchymal transition (EMT) is known to be important in regulating the behaviour of cancer cells enabling them to acquire stem cell characteristics or by enhancing the stem cell characteristics of cancer stem cells, resulting in these cells becoming more migratory and invasive. EMT can be driven by a number of mechanisms, including the TGF-β1 signalling pathway and/or by hypoxia. However, these drivers of EMT differ in their actions in regulating side population (SP) cell behaviour, even within SPs isolated from the same tissue. In this study we examined CoCl<sub>2</sub> exposure and TGF-β driven EMT on SP cells of the MDA-MB-231 and MCF7 breast cancer cell lines. Both TGF-β1 and CoCl<sub>2</sub> treatment led to the depletion of MDA-MB-231 SP. Whilst TGF-β1 treatment significantly reduced the MCF7 SP cells, CoCl<sub>2</sub> exposure led to a significant increase. Single cell analysis revealed that CoCl<sub>2</sub> exposure of MCF7 SP leads to increased expression of ABCG2 and HES1, both associated with multi-drug resistance. We also examined the mammosphere forming efficiency in response to CoCl<sub>2</sub> exposure in these cell lines, and saw the same effect as seen with the SP cells. We suggest that these contrasting effects are due to ERα expression and the inversely correlated expression of TGFB-RII, which is almost absent in the MCF7 cells. Understanding the EMT-mediated mechanisms of the regulation of SP cells could enable the identification of new therapeutic targets in breast cancer. |
| first_indexed | 2024-03-11T09:03:12Z |
| format | Article |
| id | doaj.art-92d421340f7a489084ec9baaecc6dd38 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T09:03:12Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-92d421340f7a489084ec9baaecc6dd382023-11-16T19:36:18ZengMDPI AGCancers2072-66942023-02-01154110810.3390/cancers15041108Hypoxia-Driven TGFβ Modulation of Side Population Cells in Breast Cancer: The Potential Role of ERαParaskevi Mallini0Miaojuan Chen1Kamilla Mahkamova2Thomas W. J. Lennard3Yue Pan4Dan Wei5Katherine Stemke-Hale6John A. Kirby7Gendie E. Lash8Annette Meeson9Biosciences Institute, International Centre for Life, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UKGuangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Jinsui Road, Tianhe, Guangzhou 510623, ChinaBiosciences Institute, International Centre for Life, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UKNorthern Institute for Cancer Research, Newcastle University, 3rd Floor William Leech Building, Framlington Place, Newcastle upon Tyne NE2 4HH, UKGuangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Jinsui Road, Tianhe, Guangzhou 510623, ChinaGuangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Jinsui Road, Tianhe, Guangzhou 510623, ChinaDepartment of Systems Biology, MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USATranslational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, 3rd Floor William Leech Building, Framlington Place, Newcastle upon Tyne NE2 4HH, UKGuangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Jinsui Road, Tianhe, Guangzhou 510623, ChinaBiosciences Institute, International Centre for Life, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UKEpithelial-to-mesenchymal transition (EMT) is known to be important in regulating the behaviour of cancer cells enabling them to acquire stem cell characteristics or by enhancing the stem cell characteristics of cancer stem cells, resulting in these cells becoming more migratory and invasive. EMT can be driven by a number of mechanisms, including the TGF-β1 signalling pathway and/or by hypoxia. However, these drivers of EMT differ in their actions in regulating side population (SP) cell behaviour, even within SPs isolated from the same tissue. In this study we examined CoCl<sub>2</sub> exposure and TGF-β driven EMT on SP cells of the MDA-MB-231 and MCF7 breast cancer cell lines. Both TGF-β1 and CoCl<sub>2</sub> treatment led to the depletion of MDA-MB-231 SP. Whilst TGF-β1 treatment significantly reduced the MCF7 SP cells, CoCl<sub>2</sub> exposure led to a significant increase. Single cell analysis revealed that CoCl<sub>2</sub> exposure of MCF7 SP leads to increased expression of ABCG2 and HES1, both associated with multi-drug resistance. We also examined the mammosphere forming efficiency in response to CoCl<sub>2</sub> exposure in these cell lines, and saw the same effect as seen with the SP cells. We suggest that these contrasting effects are due to ERα expression and the inversely correlated expression of TGFB-RII, which is almost absent in the MCF7 cells. Understanding the EMT-mediated mechanisms of the regulation of SP cells could enable the identification of new therapeutic targets in breast cancer.https://www.mdpi.com/2072-6694/15/4/1108breast cancer stem cellscytokinesCoCl<sub>2</sub>TGFβside population cells4-hydroxytamoxifen |
| spellingShingle | Paraskevi Mallini Miaojuan Chen Kamilla Mahkamova Thomas W. J. Lennard Yue Pan Dan Wei Katherine Stemke-Hale John A. Kirby Gendie E. Lash Annette Meeson Hypoxia-Driven TGFβ Modulation of Side Population Cells in Breast Cancer: The Potential Role of ERα Cancers breast cancer stem cells cytokines CoCl<sub>2</sub> TGFβ side population cells 4-hydroxytamoxifen |
| title | Hypoxia-Driven TGFβ Modulation of Side Population Cells in Breast Cancer: The Potential Role of ERα |
| title_full | Hypoxia-Driven TGFβ Modulation of Side Population Cells in Breast Cancer: The Potential Role of ERα |
| title_fullStr | Hypoxia-Driven TGFβ Modulation of Side Population Cells in Breast Cancer: The Potential Role of ERα |
| title_full_unstemmed | Hypoxia-Driven TGFβ Modulation of Side Population Cells in Breast Cancer: The Potential Role of ERα |
| title_short | Hypoxia-Driven TGFβ Modulation of Side Population Cells in Breast Cancer: The Potential Role of ERα |
| title_sort | hypoxia driven tgfβ modulation of side population cells in breast cancer the potential role of erα |
| topic | breast cancer stem cells cytokines CoCl<sub>2</sub> TGFβ side population cells 4-hydroxytamoxifen |
| url | https://www.mdpi.com/2072-6694/15/4/1108 |
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