ArticleProceedings of the National Academy of Sciences of the United States of America2021
Therapeutic inhibition of USP9x-mediated Notch signaling in triple-negative breast cancer.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 62 citations in OpenAlex.
- Gene expression alterations predict the pathological complete response in triple-negative breast cancer exploratory analysis of the NACATRINE trial.Scientific reports · 2023Trial
- HER2 Heterogeneous Breast Cancer Models Reveal Novel Therapeutic Targets and Subclonal Dynamics during Evolution to Resistance to HER2-Targeted Therapies.Cancer discovery · 2026Article
- Cancer stem cell plasticity: mechanisms, immune microenvironment crosstalk, and therapeutic implications.Journal of hematology & oncology · 2026Review
- Chaperone-Mediated Autophagic Degradation of USP9X in Macrophages Exacerbates Postmyocardial Infarction Inflammation and Cardiac Dysfunction.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The dual role of the Notch signaling pathway in digestive system cancers.European journal of medical research · 2026Review
- The role of pluripotency regulators in triple-negative breast cancer immune response.Frontiers in genetics · 2026Review
- Targeting ubiquitination in disease and therapy.Signal transduction and targeted therapy · 2025Review
- Cytokine Networks in Triple-Negative Breast Cancer: Mechanisms, Therapeutic Targets, and Emerging Strategies.Biomedicines · 2025Review
- Downregulation of USP9X in the DG Region of the Hippocampus Leads to AD-Like Cognitive Dysfunction in Mice.CNS neuroscience & therapeutics · 2025Article
- NOTCH1 inhibition enhances immunogenicity and sensitizes triple-negative breast cancer to immune checkpoint inhibitors.Breast cancer research : BCR · 2025Article
- Key roles of ubiquitination in regulating critical regulators of cancer stem cell functionality.Genes & diseases · 2025Review
- Tribbles Pseudokinase 3 Converts Sorafenib Therapy to Neutrophil-Mediated Lung Metastasis in Hepatocellular Carcinoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Ubiquitin-Specific Protease Inhibitors for Cancer Therapy: Recent Advances and Future Prospects.Biomolecules · 2025Review
- Deubiquitinase USP37 enhances the anti-HIV-2/SIV ability of the host restriction factor SAMHD1.Journal of virology · 2025Article
- Action and therapeutic targets of folliculin interacting protein 1: a novel signaling mechanism in redox regulation.Frontiers in cell and developmental biology · 2025Review
- Roles of deubiquitinases in urologic cancers (Review).Oncology letters · 2024Review
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- NOTCH1 mitochondria localization during heart development promotes mitochondrial metabolism and the endothelial-to-mesenchymal transition in mice.Nature communications · 2024Article
- Caspase-1-dependent spatiality in triple-negative breast cancer and response to immunotherapy.Nature communications · 2024Article
- Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Triple-negative breast cancer (TNBC) is a breast cancer subtype that lacks targeted treatment options. The activation of the Notch developmental signaling pathway, which is a feature of TNBC, results in the secretion of proinflammatory cytokines and the recruitment of protumoral macrophages to the tumor microenvironment. While the Notch pathway is an obvious therapeutic target, its activity is ubiquitous, and predictably, anti-Notch therapies are burdened with significant on-target side effects. Previously, we discovered that, under conditions of cellular stress commonly found in the tumor microenvironment, the deubiquitinase USP9x forms a multiprotein complex with the pseudokinase tribbles homolog 3 (TRB3) that together activate the Notch pathway. Herein, we provide preclinical studies that support the potential of therapeutic USP9x inhibition to deactivate Notch. Using a murine TNBC model, we show that USP9x knockdown abrogates Notch activation, reducing the production of the proinflammatory cytokines, C-C motif chemokine ligand 2 (CCL2) and interleukin-1 beta (IL-1β). Concomitant with these molecular changes, a reduction in tumor inflammation, the augmentation of antitumor immune response, and the suppression of tumor growth were observed. The pharmacological inhibition of USP9x using G9, a partially selective, small-molecule USP9x inhibitor, reduced Notch activity, remodeled the tumor immune landscape, and reduced tumor growth without associated toxicity. Proving the role of Notch, the ectopic expression of the activated Notch1 intracellular domain rescued G9-induced effects. This work supports the potential of USP9x inhibition to target Notch in metabolically vulnerable tissues like TNBC, while sparing normal Notch-dependent tissues.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.