ArticleCell research2024
ZNF689 deficiency promotes intratumor heterogeneity and immunotherapy resistance in triple-negative breast cancer.
Article in Cell research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 35 citations in OpenAlex.
- Mobilizing antigen-presenting mast cells in anti-PD-1-refractory triple-negative breast cancer: a phase 2 trial.Nature medicine · 2025Trial
- Extensive binding of poorly characterized human transcription factors to genomic dark matter.Nature communications · 2026Article
- Cancer drug response and resistance: molecular mechanisms and combating strategies.Signal transduction and targeted therapy · 2026Review
- Enzymatic activity-independent NANS stabilizes LATS2 to drive growth and therapeutic resistance in HR+/HER2- breast cancer.Nature communications · 2026Article
- ZNF689 loss impairs homologous recombination sensitizing triple-negative breast cancer to combined PARP and PD-L1 inhibition.Nature communications · 2026Article
- Geospatial genetic evolution and phenotypic plasticity in triple-negative breast cancer.Genome medicine · 2026Article
- Factors influencing the incidence of postoperative lymphedema in patients with locally advanced triple-negative breast cancer.World journal of surgical oncology · 2026Article
- Biomarker identification of triple negative breast cancer subtypes using machine learning.NPJ systems biology and applications · 2026Article
- Identify high-risk patients of T1-2N1M0 breast cancer who benefit from postmastectomy radiotherapy: a dual-center retrospective propensity score-matched study.European radiology · 2026Article
- Zinc finger proteins (ZFPs) in health and disease.Molecular biomedicine · 2026Review
- Comprehensive genomic profiling of triple-negative breast cancer metastases identifies role of PKD1 in immunotherapy resistance.The Journal of clinical investigation · 2026Article
- Growth factors maintain intratumoral heterogeneity and drive therapeutic resistance in triple-negative breast cancer.Cell reports · 2026Article
- Article
- Gas Vesicles and Acoustic Protein Nanostructures in Molecular Ultrasound Nanomedicine: Translational Archetypes, Biomaterial Design, and Barriers to Clinical Realization.International journal of nanomedicine · 2026Review
- Emerging Approaches in Breast Cancer: From Molecular Mechanisms to Diagnosis and Therapeutic Strategies.Oncology research · 2026Review
- Review
- Protective NK Cell Reservoir Based on DNA Supramolecular Hydrogel for Enhanced Triple-Negative Breast Cancer Therapy.Research (Washington, D.C.) · 2026Article
- Mapping the Multifaceted Roles of ZNF280A: Insights into Prognosis, Immunity, and Function Across Pan-Cancer.Current medicinal chemistry · 2026Review
- Pan-cancer bone metastasis atlas at single-cell resolution identifies a distinct tumor-associated macrophage subset for mediating Denosumab-induced immunosensitization in lung cancer bone metastasis.International journal of biological sciences · 2026Article
- Tripartite motif-containing protein 28 promotes drug resistance to bortezomib in gastric cancer through proteasome activity regulation.CytoJournal · 2026Article
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
Abstract
Triple-negative breast cancer (TNBC) is an aggressive disease characterized by remarkable intratumor heterogeneity (ITH), which poses therapeutic challenges. However, the clinical relevance and key determinant of ITH in TNBC are poorly understood. Here, we comprehensively characterized ITH levels using multi-omics data across our center's cohort (n = 260), The Cancer Genome Atlas cohort (n = 134), and four immunotherapy-treated cohorts (n = 109). Our results revealed that high ITH was associated with poor patient survival and immunotherapy resistance. Importantly, we identified zinc finger protein 689 (ZNF689) deficiency as a crucial determinant of ITH formation. Mechanistically, the ZNF689-TRIM28 complex was found to directly bind to the promoter of long interspersed element-1 (LINE-1), inducing H3K9me3-mediated transcriptional silencing. ZNF689 deficiency reactivated LINE-1 retrotransposition to exacerbate genomic instability, which fostered ITH. Single-cell RNA sequencing, spatially resolved transcriptomics and flow cytometry analysis confirmed that ZNF689 deficiency-induced ITH inhibited antigen presentation and T-cell activation, conferring immunotherapy resistance. Pharmacological inhibition of LINE-1 significantly reduced ITH, enhanced antitumor immunity, and eventually sensitized ZNF689-deficient tumors to immunotherapy in vivo. Consistently, ZNF689 expression positively correlated with favorable prognosis and immunotherapy response in clinical samples. Altogether, our study uncovers a previously unrecognized mechanism underlying ZNF689 deficiency-induced ITH and suggests LINE-1 inhibition combined with immunotherapy as a novel treatment strategy for TNBC.
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