ArticleEBioMedicine2019
Targeting SET to restore PP2A activity disrupts an oncogenic CIP2A-feedforward loop and impairs triple negative breast cancer progression.
Article in EBioMedicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 52 citations in OpenAlex.
- Phosphoproteomic dysregulation promotes tumor proliferation in Cushing's disease.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Sp1 mechanotransduction regulates breast cancer cell invasion in engineered viscoelastic extracellular matrices.Biomaterials · 2026Article
- The novel endogenous micropeptide XLH-36 binds Gemin4 to promote triple-negative breast cancer metastasis.Oncogene · 2026Article
- Targeting SET to counteract Lyn activation demonstrates anti-cancer potential in diffuse large B-cell lymphoma.Clinical and experimental medicine · 2025Article
- The Emerging Role of the Cancerous Inhibitor of Protein Phosphatase 2A in Pulmonary Diseases.Medicina (Kaunas, Lithuania) · 2025Review
- Mechanistic Insights and Clinical Implications of ELK1 in Solid Tumors: A Narrative Review.Cells · 2025Review
- Mutant PP2A Induces IGFBP2 Secretion to Promote Development of High-Grade Uterine Cancer.Cancer research · 2025Article
- Pan-cancer transcriptome analysis reveals widespread regulation through alternative tandem transcription initiation.Science advances · 2024Article
- CIP2A induces PKM2 tetramer formation and oxidative phosphorylation in non-small cell lung cancer.Cell discovery · 2024Article
- Adverse Crosstalk between Extracellular Matrix Remodeling and Ferroptosis in Basal Breast Cancer.Cells · 2023Article
- Circular MTHFD2L RNA-encoded CM-248aa inhibits gastric cancer progression by targeting the SET-PP2A interaction.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- The Effects of Protein Phosphatase 2A Activation with Novel Tricyclic Sulfonamides on Hepatoblastoma.Journal of pediatric surgery · 2023Article
- Protein Phosphatase 2a Inhibits Gastric Cancer Cell Glycolysis by Reducing MYC Signaling.Cell biochemistry and biophysics · 2023Article
- Strategies to target the cancer driver MYC in tumor cells.Frontiers in oncology · 2023Review
- CIP2A as a Key Regulator for AKT Phosphorylation Has Partial Impact Determining Clinical Outcome in Breast Cancer.Journal of clinical medicine · 2022Article
- PP2A is activated by cytochromeComputational and structural biotechnology journal · 2022Article
- Mitochondrial cytochrome c shot towards histone chaperone condensates in the nucleus.FEBS open bio · 2021Review
- Deregulation of protein phosphatase 2A inhibitor SET is associated with malignant progression in breast cancer.Scientific reports · 2021Article
- Targeting of SET/I2PP2A oncoprotein inhibits Gli1 transcription revealing a new modulator of Hedgehog signaling.Scientific reports · 2021Article
- Expression pattern and prognostic impact of glycoprotein non-metastatic B (GPNMB) in triple-negative breast cancer.Scientific reports · 2021Article
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Authors and funding
11 authors at 6 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundTriple-negative breast cancer (TNBC) remains difficult to be targeted. SET and cancerous inhibitor of protein phosphatase 2A (CIP2A) are intrinsic protein-interacting inhibitors of protein phosphatase 2A (PP2A) and frequently overexpressed in cancers, whereas reactivating PP2A activity has been postulated as an anti-cancer strategy. Here we explored this strategy in TNBC.
methodsData from The Cancer Genome Atlas (TCGA) database was analyzed. TNBC cell lines were used for in vitro studies. Cell viability was examined by MTT assay. The apoptotic cells were examined by flow cytometry and Western blot. A SET-PP2A protein-protein interaction antagonist TD19 was used to disrupt signal transduction. In vivo efficacy of TD19 was tested in MDA-MB-468-xenografted animal model.
findingsTCGA data revealed upregulation of SET and CIP2A and positive correlation of these two gene expressions in TNBC tumors. Ectopic SET or CIP2A increased cell viability, migration, and invasion of TNBC cells. Notably ERK inhibition increased PP2A activity. ERK activation is known crucial for Elk-1 activity, a transcriptional factor regulating CIP2A expression, we hypothesized an oncogenic feedforward loop consisting of pERK/pElk-1/CIP2A/PP2A. This loop was validated by knockdown of PP2A and ectopic expression of Elk-1, showing reciprocal changes in loop members. In addition, ectopic expression of SET increased pAkt, pERK, pElk-1 and CIP2A expressions, suggesting a positive linkage between SET and CIP2A signaling. Moreover, TD19 disrupted this CIP2A-feedforward loop by restoring PP2A activity, demonstrating in vitro and in vivo anti-cancer activity. Mechanistically, TD19 downregulated CIP2A mRNA via inhibiting pERK-mediated Elk-1 nuclear translocation thereby decreased Elk-1 binding to the CIP2A promoter.
interpretationThese findings suggested that a novel oncogenic CIP2A-feedforward loop contributes to TNBC progression and targeting SET to disrupt this oncogenic CIP2A loop showed therapeutic potential in TNBC.
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