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Updated: Aug 5, 2026
11:02
In vivo Bioluminescence Imaging of Tumor Hypoxia Dynamics of Breast Cancer Brain Metastasis in a Mouse Model
Published on: October 3, 2011
Intratumoral Hypoxia Triggers Mitochondrial BHLHE40 ROS Sensing Pathway to Promote Radioresistance in Triple-Negative
Jia Liu1, Ziliang Nie1,2, Xi Chen1
1Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 27, 2026
Summary
Hypoxia in triple-negative breast cancer triggers reactive oxygen species (ROS). The study identifies BHLHE40 as a novel mitochondrial ROS sensor, crucial for hypoxia-induced radioresistance in TNBC.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Intratumoral hypoxia is a key feature of triple-negative breast cancer (TNBC).
- Hypoxia drives treatment resistance and reactive oxygen species (ROS) production, but sensing mechanisms are unclear.
- ROS regulate transcription factors via cysteine oxidation, yet compartmentalization poses challenges.
Purpose of the Study:
- To identify novel mechanisms linking hypoxia-induced ROS to therapeutic resistance in TNBC.
- To investigate the role of BHLHE40 as a potential mitochondrial ROS sensor.
- To explore BHLHE40's function in hypoxia-driven radioresistance.
Main Methods:
- Identification of BHLHE40 as a mitochondrial protein.
- Analysis of ROS-dependent cysteine oxidation and homodimerization of BHLHE40.
- Investigation of hypoxia-inducible factor (HIF)-mediated transcriptional regulation of BHLHE40.
- Functional studies assessing BHLHE40's role in radioresistance.
Main Results:
- BHLHE40 is identified as a novel mitochondrial sensor of hypoxia-induced ROS.
- Mitochondrial BHLHE40 undergoes ROS-dependent oxidation and forms disulfide-linked homodimers.
- Hypoxia upregulates BHLHE40 via post-translational modification and HIF-dependent transcription.
- BHLHE40 promotes radioresistance by activating antioxidant systems and inhibiting ROS effects.
Conclusions:
- BHLHE40 acts as a critical mitochondrial ROS sensor in hypoxic TNBC.
- BHLHE40 plays a key role in mediating hypoxia-induced radioresistance.
- Targeting BHLHE40 may offer a strategy to overcome radioresistance in TNBC.
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