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Updated: Jul 23, 2025
06:54
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
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GTP Cyclohydrolase Drives Breast Cancer Development and Promotes EMT in an Enzyme-Independent Manner
Zijing Wang1,2, Nan Zhang1,2, Miao Zhang1,3
1Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
Cancer Research
|July 18, 2023
Summary
GTP cyclohydrolase (GCH1) acts as an oncogene in breast cancer, promoting tumor growth independently of its enzyme activity. Targeting GCH1 offers new therapeutic strategies for breast cancer treatment.
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- GTP cyclohydrolase (GCH1) is key in tetrahydrobiopterin (BH4) synthesis, a process vital for neurotransmission and vascular tone.
- BH4's role as an oncometabolite in tumor growth is debated, with GCH1's specific contribution to breast cancer development unclear.
Purpose of the Study:
- To investigate the role of GCH1 in breast cancer progression and its underlying mechanisms.
- To explore the potential of GCH1 as a therapeutic target in breast cancer.
Main Methods:
- Assessed GCH1's effect on triple-negative breast cancer (TNBC) and HER2+ breast cancer cell growth and transformation.
- Investigated GCH1's interaction with vimentin (Vim) and the role of HSP90.
- Analyzed the impact of GCH1 ablation on tumor growth, signaling pathways (EGFR/ERK, p53), and sensitivity to HSP90 inhibition and endocrine treatments.
Main Results:
- GCH1 potentiated the growth of TNBC and HER2+ breast cancer and transformed normal breast cells.
- GCH1 induced epithelial-to-mesenchymal transition (EMT) by binding to vimentin, independent of its enzymatic activity.
- GCH1 ablation impaired tumor growth, suppressed Vim, inhibited EGFR/ERK signaling, and activated the p53 pathway, increasing sensitivity to therapies.
Conclusions:
- GCH1 possesses an enzyme-independent oncogenic function in breast cancer.
- GCH1 is a potential therapeutic target, and its deficiency sensitizes tumors to HSP90 inhibition and endocrine treatments.
- High GCH1 expression correlates with poor breast cancer survival, highlighting its prognostic significance.
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