NR3C2 suppresses triple-negative breast cancer progression by regulating mitochondrial ROS homeostasis via NDUFB3.
- 1Department of Breast Surgery, The Second Affiliated Hospital of Fujian Medical University, No 34, North Zhongshan Road, Licheng District, Quanzhou City, Fujian, 362000, China.
- 2Department of Breast Surgery, The Second Affiliated Hospital of Fujian Medical University, No 34, North Zhongshan Road, Licheng District, Quanzhou City, Fujian, 362000, China. Electronic address: [email protected].
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by high molecular heterogeneity and a lack of effective targeted therapies. Increasing evidence indicates that metabolic reprogramming and redox homeostasis are critical determinants of TNBC progression; however, the transcriptional mechanisms linking these processes to mitochondrial function remain incompletely understood. In this study, integrative bioinformatics analyses identified nuclear receptor subfamily 3 group C member 2 (NR3C2) as a potential regulatory factor in TNBC. NR3C2 expression was significantly decreased in TNBC and was associated with patient prognosis. Functional assays demonstrated that NR3C2 overexpression markedly inhibited cell proliferation and migration in vitro and suppressed tumor growth and dissemination in zebrafish xenograft models. Mechanistically, RNA sequencing identified NDUFB3, an accessory subunit of mitochondrial complex I, as a downstream target of NR3C2. Dual-luciferase reporter assays further confirmed that NR3C2 directly regulates NDUFB3 transcription. Functional analyses revealed that NR3C2 modulates mitochondrial activity, as evidenced by increased mitochondrial membrane potential and complex I activity, accompanied by reduced ATP production and elevated reactive oxygen species (ROS) levels. Notably, NR3C2-induced ROS accumulation promoted apoptosis, whereas these effects were partially reversed by NDUFB3 knockdown or treatment with the ROS scavenger N-acetylcysteine (NAC). Consistently, in vivo experiments demonstrated that NR3C2 suppresses tumor growth and metastasis in a ROS-dependent manner. Collectively, these findings indicate that NR3C2 inhibits TNBC progression by regulating mitochondrial function and ROS homeostasis, at least in part through NDUFB3. This study provides new insights into the interplay between transcriptional regulation and mitochondrial redox balance and highlights NR3C2 as a potential therapeutic target for TNBC.
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BibTeX
@article{shi2026nr3c2,
title = {{NR3C2 suppresses triple-negative breast cancer progression by regulating mitochondrial ROS homeostasis via NDUFB3.}},
author = {Haihong Shi and Xian Zeng and Qiaonan Guo and Jianqing Lin},
journal = {Translational oncology},
year = {2026},
month = oct,
doi = {10.1016/j.tranon.2026.103072},
url = {https://europepmc.org/article/MED/42874536},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - NR3C2 suppresses triple-negative breast cancer progression by regulating mitochondrial ROS homeostasis via NDUFB3.
AU - Haihong Shi
AU - Xian Zeng
AU - Qiaonan Guo
AU - Jianqing Lin
PY - 2026
DA - 2026/10/14
JO - Translational oncology
DO - 10.1016/j.tranon.2026.103072
UR - https://europepmc.org/article/MED/42874536
AB - Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by high molecular heterogeneity and a lack of effective targeted therapies. Increasing evidence indicates that metabolic reprogramming and redox homeostasis are critical determinants of TNBC progression; however, the transcriptional mechanisms linking these processes to mitochondrial function remain incompletely understood. In this study, integrative bioinformatics analyses identified nuclear receptor subfamily 3 group C member 2 (NR3C2) as a potential regulatory factor in TNBC. NR3C2 expression was significantly decreased in TNBC and was associated with patient prognosis. Functional assays demonstrated that NR3C2 overexpression markedly inhibited cell proliferation and migration in vitro and suppressed tumor growth and dissemination in zebrafish xenograft models. Mechanistically, RNA sequencing identified NDUFB3, an accessory subunit of mitochondrial complex I, as a downstream target of NR3C2. Dual-luciferase reporter assays further confirmed that NR3C2 directly regulates NDUFB3 transcription. Functional analyses revealed that NR3C2 modulates mitochondrial activity, as evidenced by increased mitochondrial membrane potential and complex I activity, accompanied by reduced ATP production and elevated reactive oxygen species (ROS) levels. Notably, NR3C2-induced ROS accumulation promoted apoptosis, whereas these effects were partially reversed by NDUFB3 knockdown or treatment with the ROS scavenger N-acetylcysteine (NAC). Consistently, in vivo experiments demonstrated that NR3C2 suppresses tumor growth and metastasis in a ROS-dependent manner. Collectively, these findings indicate that NR3C2 inhibits TNBC progression by regulating mitochondrial function and ROS homeostasis, at least in part through NDUFB3. This study provides new insights into the interplay between transcriptional regulation and mitochondrial redox balance and highlights NR3C2 as a potential therapeutic target for TNBC.
SN - 1936-5233
ER -