Yuan Shyng-Shiou F, Vadhan Anupama, Nguyen Hieu D H, Chen Pang-Yu, Tseng Chih-Huang, Wu Ching-Hu, Chen Yu-Chieh, Wu Yi-Chia, Hu Stephen Chu-Sung, Lo Steven, Hou Ming-Feng, Wang Yen-Yun
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.
Cancer Metab. 2025 May 29;13(1):26. doi: 10.1186/s40170-025-00397-z.
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.
乳腺癌仍然是全球女性中最常见的恶性肿瘤，其复杂性与肿瘤细胞内的基因变异和代谢改变有关。本研究调查了三羧酸（TCA）循环中的关键酶富马酸水合酶（FH）在乳腺癌进展中的作用。我们的研究结果显示，FH的mRNA和蛋白水平在乳腺癌组织中显著上调，且与患者预后不良和肿瘤侵袭性特征相关。通过体外和体内模型，我们证明FH过表达通过代谢重编程和增加活性氧（ROS）生成来增强乳腺癌细胞的增殖、迁移和侵袭。此外，我们确定基质金属蛋白酶1（MMP1）是FH的下游效应因子，与p21下调有关，阐明了一条影响肿瘤行为的新调控途径。有趣的是，与它在其他癌症类型中的抑癌作用不同，本研究突出了FH在乳腺癌中的致癌潜力。我们的结果表明，FH通过催化和非催化机制增强癌细胞的活力和侵袭性。这项工作不仅强调了乳腺癌细胞的代谢适应性，还提出FH作为乳腺癌管理的潜在生物标志物和治疗靶点。
