Oncogenic role of fumarate hydratase in breast cancer: metabolic reprogramming and mechanistic insights
Abstract Breast cancer remains the most prevalent malignancy among women globally, with its complexity linked to genetic variations and metabolic alterations within tumor cells. This study investigates the role of fumarate hydratase (FH), a key enzyme in the tricarboxylic acid (TCA) cycle, in breast...
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| Format: | Article |
| Language: | English |
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BMC
2025-05-01
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| Series: | Cancer & Metabolism |
| Online Access: | https://doi.org/10.1186/s40170-025-00397-z |
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| author | Shyng-Shiou F. Yuan Anupama Vadhan Hieu D. H. Nguyen Pang-Yu Chen Chih-Huang Tseng Ching-Hu Wu Yu-Chieh Chen Yi-Chia Wu Stephen Chu‐Sung Hu Steven Lo Ming-Feng Hou Yen-Yun Wang |
| author_facet | Shyng-Shiou F. Yuan Anupama Vadhan Hieu D. H. Nguyen Pang-Yu Chen Chih-Huang Tseng Ching-Hu Wu Yu-Chieh Chen Yi-Chia Wu Stephen Chu‐Sung Hu Steven Lo Ming-Feng Hou Yen-Yun Wang |
| author_sort | Shyng-Shiou F. Yuan |
| collection | DOAJ |
| description | Abstract Breast cancer remains the most prevalent malignancy among women globally, with its complexity linked to genetic variations and metabolic alterations within tumor cells. This study investigates the role of fumarate hydratase (FH), a key enzyme in the tricarboxylic acid (TCA) cycle, in breast cancer progression. Our findings reveal that FH mRNA and protein levels are significantly upregulated in breast cancer tissues and correlate with poor patient prognosis and aggressive tumor characteristics. Using in vitro and in vivo models, we demonstrate that FH overexpression enhances breast cancer cell proliferation, migration, and invasion through metabolic reprogramming and by increasing reactive oxygen species (ROS) production. Furthermore, we identify matrix metalloproteinase 1 (MMP1) as a downstream effector of FH, linked to p21 downregulation, elucidating a novel regulatory pathway influencing tumor behavior. Interestingly, unlike its tumor-suppressing role in other cancer types, this study highlights FH's oncogenic potential in breast cancer. Our results suggest that FH enhances cancer cell viability and aggressiveness via both catalytic and non-catalytic mechanisms. This work not only underscores the metabolic adaptations of breast cancer cells but also proposes FH as a potential biomarker and therapeutic target for breast cancer management. |
| format | Article |
| id | doaj-art-476d27aae63a47c097b3d4975ec4cddf |
| institution | DOAJ |
| issn | 2049-3002 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer & Metabolism |
| spelling | doaj-art-476d27aae63a47c097b3d4975ec4cddf2025-08-20T03:22:03ZengBMCCancer & Metabolism2049-30022025-05-0113111710.1186/s40170-025-00397-zOncogenic role of fumarate hydratase in breast cancer: metabolic reprogramming and mechanistic insightsShyng-Shiou F. Yuan0Anupama Vadhan1Hieu D. H. Nguyen2Pang-Yu Chen3Chih-Huang Tseng4Ching-Hu Wu5Yu-Chieh Chen6Yi-Chia Wu7Stephen Chu‐Sung Hu8Steven Lo9Ming-Feng Hou10Yen-Yun Wang11Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical UniversityGraduate Institute of Medicine, College of Medicine, Kaohsiung Medical UniversitySchool of Dentistry, College of Dental Medicine, Kaohsiung Medical UniversityGraduate Institute of Medicine, College of Medicine, Kaohsiung Medical UniversitySchool of Dentistry, College of Dental Medicine, Kaohsiung Medical UniversityDepartment of Obstetrics and Gynecology, Kaohsiung Medical University HospitalDepartment of Obstetrics and Gynecology, Kaohsiung Medical University HospitalSchool of Medicine, College of Medicine, Kaohsiung Medical UniversityDepartment of Dermatology, College of Medicine, Kaohsiung Medical UniversityCanniesburn Regional Plastic Surgery and Burns Unit, College of Medical, Veterinary and Life Sciences, University of GlasgowDivision of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University HospitalDepartment of Medical Research, Kaohsiung Medical University HospitalAbstract Breast cancer remains the most prevalent malignancy among women globally, with its complexity linked to genetic variations and metabolic alterations within tumor cells. This study investigates the role of fumarate hydratase (FH), a key enzyme in the tricarboxylic acid (TCA) cycle, in breast cancer progression. Our findings reveal that FH mRNA and protein levels are significantly upregulated in breast cancer tissues and correlate with poor patient prognosis and aggressive tumor characteristics. Using in vitro and in vivo models, we demonstrate that FH overexpression enhances breast cancer cell proliferation, migration, and invasion through metabolic reprogramming and by increasing reactive oxygen species (ROS) production. Furthermore, we identify matrix metalloproteinase 1 (MMP1) as a downstream effector of FH, linked to p21 downregulation, elucidating a novel regulatory pathway influencing tumor behavior. Interestingly, unlike its tumor-suppressing role in other cancer types, this study highlights FH's oncogenic potential in breast cancer. Our results suggest that FH enhances cancer cell viability and aggressiveness via both catalytic and non-catalytic mechanisms. This work not only underscores the metabolic adaptations of breast cancer cells but also proposes FH as a potential biomarker and therapeutic target for breast cancer management.https://doi.org/10.1186/s40170-025-00397-z |
| spellingShingle | Shyng-Shiou F. Yuan Anupama Vadhan Hieu D. H. Nguyen Pang-Yu Chen Chih-Huang Tseng Ching-Hu Wu Yu-Chieh Chen Yi-Chia Wu Stephen Chu‐Sung Hu Steven Lo Ming-Feng Hou Yen-Yun Wang Oncogenic role of fumarate hydratase in breast cancer: metabolic reprogramming and mechanistic insights Cancer & Metabolism |
| title | Oncogenic role of fumarate hydratase in breast cancer: metabolic reprogramming and mechanistic insights |
| title_full | Oncogenic role of fumarate hydratase in breast cancer: metabolic reprogramming and mechanistic insights |
| title_fullStr | Oncogenic role of fumarate hydratase in breast cancer: metabolic reprogramming and mechanistic insights |
| title_full_unstemmed | Oncogenic role of fumarate hydratase in breast cancer: metabolic reprogramming and mechanistic insights |
| title_short | Oncogenic role of fumarate hydratase in breast cancer: metabolic reprogramming and mechanistic insights |
| title_sort | oncogenic role of fumarate hydratase in breast cancer metabolic reprogramming and mechanistic insights |
| url | https://doi.org/10.1186/s40170-025-00397-z |
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