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Publications

Journal Article Epublish 3 citations

PubMed: 40437625 DOI: 10.1186/s40170-025-00397-z

Oncogenic role of fumarate hydratase in breast cancer: metabolic reprogramming and mechanistic insights.

Cancer Metab 13(1):26

Authors: 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

Affiliations

  • Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan. Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan. Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan. Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, 807, Taiwan. Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, Center for Intelligent Drug Systems and Smart Biodevices (IDS2B), National Yang Ming Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300, Taiwan.
  • Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • National Center for Geriatrics and Welfare Research, National Health Research Institutes, No. 8, Xuefu W. RdYunlin County 632, Huwei Township, Taiwan.
  • School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
  • Division of Oral Pathology & Maxillofacial Radiology, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.
  • Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.
  • School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
  • Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.
  • Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.
  • Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
  • Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.
  • Canniesburn Regional Plastic Surgery and Burns Unit, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G4 0SFG12 8QQ, UK.
  • Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
  • Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.
  • Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
  • School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.

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.

MeSH

Cells, Breast Neoplasms, Neoplasms, Fumarates, Breast, Fumarate Hydratase