Work

NR3C2 suppresses triple-negative breast cancer progression by regulating mitochondrial ROS homeostasis via NDUFB3

Year: 2026

Type: article

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.

Source: Translational Oncology

DOI: 10.1016/j.tranon.2026.103072

Authors: Haihong Shi, Xian Zeng, Qiaonan Guo, Jianqing Lin

Institutions: Fujian Medical University, Second Affiliated Hospital of Fujian Medical University

Language: English

Topic: Mitochondrial Function and Pathology

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,390