DUSP4 enhances therapeutic sensitivity in HER2-positive breast cancer by inhibiting the G6PD pathway and ROS metabolism by interacting with ALDOB.
Transl Oncol
; 46: 102016, 2024 Aug.
Article
em En
| MEDLINE
| ID: mdl-38843658
ABSTRACT
BACKGROUND:
Breast cancer (BC) poses a global threat, with HER2-positive BC being a particularly hazardous subtype. Despite the promise shown by neoadjuvant therapy (NAT) in improving prognosis, resistance in HER2-positive BC persists despite emerging targeted therapies. The objective of this study is to identify markers that promote therapeutic sensitivity and unravel the underlying mechanisms.METHODS:
We conducted an analysis of 86 HER2-positive BC biopsy samples pre-NAT using RNA-seq. Validation was carried out using TCGA, KaplanâMeier Plotter, and Oncomine databases. Phenotype verification utilized IC50 assays, and prognostic validation involved IHC on tissue microarrays. RNA-seq was performed on wild-type/DUSP4-KO cells, while RTâqPCR assessed ROS pathway regulation. Mechanistic insights were obtained through IP and MS assays.RESULTS:
Our findings reveal that DUSP4 enhances therapeutic efficacy in HER2-positive BC by inhibiting the ROS pathway. Elevated DUSP4 levels correlate with increased sensitivity to HER2-targeted therapies and improved clinical outcomes. DUSP4 independently predicts disease-free survival (DFS) and overall survival (OS) in HER2-positive BC. Moreover, DUSP4 hinders G6PD activity via ALDOB dephosphorylation, with a noteworthy association with heightened ROS levels.CONCLUSIONS:
In summary, our study unveils a metabolic reprogramming paradigm in BC, highlighting DUSP4's role in enhancing therapeutic sensitivity in HER2-positive BC cells. DUSP4 interacts with ALDOB, inhibiting G6PD activity and the ROS pathway, establishing it as an independent prognostic predictor for HER2-positive BC patients.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Transl Oncol
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China
País de publicação:
Estados Unidos