ArticleNature communications2020
EZH2-mediated PP2A inactivation confers resistance to HER2-targeted breast cancer therapy.
Article in Nature communications, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 52 citations in OpenAlex.
- Targeting an ASCL1-WNT11-ERK feed-forward loop to overcome pyrotinib resistance in HER2-positive breast cancer.Materials today. Bio · 2026Article
- Impact of Trastuzumab and Pertuzumab on HER2 Localization and the Estrogen Receptor Cistrome in ER+/HER2+ Breast Cancer.bioRxiv : the preprint server for biology · 2026Article
- Discovery of XNW5004 as a novel EZH2 inhibitor that enhances anti-tumor immunity and synergizes with PD-1 blockade immunotherapy in lung adenocarcinoma.Journal of translational medicine · 2026Article
- Integrating polygenic and methylation risk scores for pleural mesothelioma risk stratification.International journal of cancer · 2026Article
- Epigenetic modifications in cancer drug resistance: molecular mechanisms and therapeutic interventions.Molecular biomedicine · 2026Review
- PRMT6-mediated EZH2 arginine methylation is critical for breast cancer development.Oncogenesis · 2026Article
- A multiomics Mendelian randomization study on PANoptosis-related genes and gastric cancer risk.The Journal of international medical research · 2026Article
- EZH2 directs HER2+ breast cancer progression through the modulation of epithelial plasticity.EMBO reports · 2026Article
- Trastuzumab-TKI combination in HER2-Positive tumors: a FAERS-Based safety profile and multimodal analysis of Tanespimycin's role in enhancing targeting of the HSP90AA1-PI3K-Akt-mTOR axis.Frontiers in pharmacology · 2026Article
- EZH2 blockade reverses doxorubicin resistance by inducing metabolic vulnerability and enhancing DNA damage in breast cancer.Frontiers in pharmacology · 2026Article
- Immunohistochemical analysis reveals increased active GSK3 and inactive PP2A levels in anaplastic thyroid cancer.Journal of diabetes and metabolic disorders · 2025Article
- Intervention of machine learning in bladder cancer research using multi-omics datasets: systematic review on biomarker identification.Discover oncology · 2025Review
- Treating human cancer by targeting EZH2.Genes & diseases · 2025Review
- Targeting Long Noncoding RNA H19 in Subchondral Bone Osteocytes and the Alleviation of Cartilage Degradation in Osteoarthritis.Arthritis & rheumatology (Hoboken, N.J.) · 2025Article
- Epigenetic regulation espeically histone modifications in breast cancer: A viable and emerging targeted therapeutic strategy.Journal of Cancer · 2025Review
- Dephosphorylation-related signature predicts the prognosis of papillary renal cell carcinoma.Translational cancer research · 2024Article
- Nuclear translocation of ISG15 regulated by PPP2R2B inhibits cisplatin resistance of bladder cancer.Cellular and molecular life sciences : CMLS · 2024Article
- New clinical trial design in precision medicine: discovery, development and direction.Signal transduction and targeted therapy · 2024Review
- HER2-targeted therapies in cancer: a systematic review.Biomarker research · 2024Review
- HOXC6 drives a therapeutically targetable pancreatic cancer growth and metastasis pathway by regulating MSK1 and PPP2R2B.Cell reports. Medicine · 2023Article
Corrections and comments
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Authors and funding
14 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
HER2-targeted therapy has yielded a significant clinical benefit in patients with HER2+ breast cancer, yet disease relapse due to intrinsic or acquired resistance remains a significant challenge in the clinic. Here, we show that the protein phosphatase 2A (PP2A) regulatory subunit PPP2R2B is a crucial determinant of anti-HER2 response. PPP2R2B is downregulated in a substantial subset of HER2+ breast cancers, which correlates with poor clinical outcome and resistance to HER2-targeted therapies. EZH2-mediated histone modification accounts for the PPP2R2B downregulation, resulting in sustained phosphorylation of PP2A targets p70S6K and 4EBP1 which leads to resistance to inhibition by anti-HER2 treatments. Genetic depletion or inhibition of EZH2 by a clinically-available EZH2 inhibitor restores PPP2R2B expression, abolishes the residual phosphorylation of p70S6K and 4EBP1, and resensitizes HER2+ breast cancer cells to anti-HER2 treatments both in vitro and in vivo. Furthermore, the same epigenetic mechanism also contributes to the development of acquired resistance through clonal selection. These findings identify EZH2-dependent PPP2R2B suppression as an epigenetic control of anti-HER2 resistance, potentially providing an opportunity to mitigate anti-HER2 resistance with EZH2 inhibitors.
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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.