ArticleOncotarget2015
p21-activated kinase group II small compound inhibitor GNE-2861 perturbs estrogen receptor alpha signaling and restores tamoxifen-sensitivity in breast cancer cells.
Article in Oncotarget, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
What it found
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Who cites it
32 citing papers in PubMed, 51 citations in OpenAlex.
- Computational Identification of New Dual PAK4 and NAMPT Inhibitors.International journal of molecular sciences · 2026Article
- Role of serine/threonine phosphatases 1 and 2A in pancreatic acinar fluid and electrolyte secretion.American journal of physiology. Gastrointestinal and liver physiology · 2026Article
- P21-activated kinase 4: a potent oncogene, molecular mechanisms and opportunities for targeted therapy.Cancer cell international · 2025Review
- Regulation of Vascular Injury and Repair by P21-Activated Kinase 1 and P21-Activated Kinase 2: Therapeutic Potential and Challenges.Biomolecules · 2024Review
- Inhibition of NAMPT by PAK4 Inhibitors.International journal of molecular sciences · 2024Article
- Expression Patterns of PAK4 and PHF8 Are Associated with the Survival of Gallbladder Carcinoma Patients.Diagnostics (Basel, Switzerland) · 2023Article
- Hyperactivation of p21-Activated Kinases in Human Cancer and Therapeutic Sensitivity.Biomedicines · 2023Review
- Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells.Acta pharmaceutica Sinica. B · 2022Article
- p21-Activated kinases as promising therapeutic targets in hematological malignancies.Leukemia · 2022Review
- Dissecting the Roles of PDCD4 in Breast Cancer.Frontiers in oncology · 2022Review
- Review
- OTUD7B stabilizes estrogen receptor α and promotes breast cancer cell proliferation.Cell death & disease · 2021Article
- Nonlinear relationship between chromatin accessibility and estradiol-regulated gene expression.Oncogene · 2021Article
- ZNF213 Facilitates ER Alpha Signaling in Breast Cancer Cells.Frontiers in oncology · 2021Article
- Recognition of physiological phosphorylation sites by p21-activated kinase 4.Journal of structural biology · 2020Article
- KPT-9274, an Inhibitor of PAK4 and NAMPT, Leads to Downregulation of mTORC2 in Triple Negative Breast Cancer Cells.Chemical research in toxicology · 2020Article
- Fisetin Modulates Human Oral Squamous Cell Carcinoma Proliferation by Blocking PAK4 Signaling Pathways.Drug design, development and therapy · 2020Article
- The deubiquitinating enzyme USP1 modulates ERα and modulates breast cancer progression.Journal of Cancer · 2020Article
- Normal mammary gland development after MMTV-Cre mediated conditional PAK4 gene depletion.Scientific reports · 2019Article
- PAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer.Nature communications · 2019Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Estrogen receptor alpha (ERα) is highly expressed in most breast cancers. Consequently, ERα modulators, such as tamoxifen, are successful in breast cancer treatment, although tamoxifen resistance is commonly observed. While tamoxifen resistance may be caused by altered ERα signaling, the molecular mechanisms regulating ERα signaling and tamoxifen resistance are not entirely clear. Here, we found that PAK4 expression was consistently correlated to poor patient outcome in endocrine treated and tamoxifen-only treated breast cancer patients. Importantly, while PAK4 overexpression promoted tamoxifen resistance in MCF-7 human breast cancer cells, pharmacological treatment with a group II PAK (PAK4, 5, 6) inhibitor, GNE-2861, sensitized tamoxifen resistant MCF-7/LCC2 breast cancer cells to tamoxifen. Mechanistically, we identified a regulatory positive feedback loop, where ERα bound to the PAK4 gene, thereby promoting PAK4 expression, while PAK4 in turn stabilized the ERα protein, activated ERα transcriptional activity and ERα target gene expression. Further, PAK4 phosphorylated ERα-Ser305, a phosphorylation event needed for the PAK4 activation of ERα-dependent transcription. In conclusion, PAK4 may be a suitable target for perturbing ERα signaling and tamoxifen resistance in breast cancer patients.
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Registered trials
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.