ArticleBritish journal of cancer2013
Regulation of tamoxifen sensitivity by a PAK1-EBP1 signalling pathway in breast cancer.
Article in British journal of cancer, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 22 citations in OpenAlex.
- PA2G4 in health and disease: An underestimated multifunctional regulator.Journal of advanced research · 2025Review
- Ebp1 p48 Promotes Oncogenic Properties in Non-Small Cell Lung Cancer Through PI3K/Akt Signaling Pathways.OncoTargets and therapy · 2025Article
- Hyperactivation of p21-Activated Kinases in Human Cancer and Therapeutic Sensitivity.Biomedicines · 2023Review
- PAK1 copy number in breast cancer-Associations with proliferation and molecular subtypes.PloS one · 2023Article
- Review
- CircLMTK2 Silencing Attenuates Gemcitabine Resistance in Pancreatic Cancer by Sponging miR-485-5p and to Target PAK1.Journal of oncology · 2022Article
- Towards Unravelling the Role of ERα-Targeting miRNAs in the Exosome-Mediated Transferring of the Hormone Resistance.Molecules (Basel, Switzerland) · 2021Article
- The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer.Nature communications · 2021Article
- Exosome-Mediated Transfer of Cancer Cell Resistance to Antiestrogen Drugs.Molecules (Basel, Switzerland) · 2018Article
- Induction of mitochondrial apoptotic pathway by raloxifene and estrogen in human endometrial stromal ThESC cell line.Archives of medical science : AMS · 2017Article
- Heregulin negatively regulates transcription of ErbB2/3 receptors via an AKT-mediated pathway.Journal of cellular physiology · 2014Article
- P21-activated kinase in inflammatory and cardiovascular disease.Cellular signalling · 2014Review
- Expression of ErbB3-binding protein-1 (EBP1) during primordial follicle formation: role of estradiol-17ß.PloS one · 2013Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundEBP1, an ErbB3-binding protein, sensitises breast cancer cells to tamoxifen in part by decreasing ErbB2 protein levels. The p21-regulated serine/threonine kinase PAK1, implicated in tamoxifen resistance, phosphorylates EBP1 in vitro and in vivo at T261. Phosphorylation of EBP1 at this site induces tamoxifen resistance. We thus postulated that inhibition of PAK1 activity, by restoring EBP1 function, could ameliorate the hormone refractory phenotype of ErbB2-overexpressing breast cancer cells.
methodsEffects of EBP1 on ErbB2 levels were measured by western blotting. Effects of EBP1 and IPA-3 on tamoxifen sensitivity were measured using a tetrazolium based cell viability assay.
resultsTransient transfection studies indicated that an EBP1 T261E mutant, which mimics EPB1 phosphorylated by PAK1, increased ErbB2 protein levels. An EBP1 T261A mutant, unable to be phosphorylated by PAK1, ameliorated PAK1-induced tamoxifen resistance, suggesting that phosphorylation of EBP1 by PAK1 contributes to tamoxifen resistance. We then tested if pharmacological inhibition of PAK1 activity might render hormone resistant cells, which endogenously overexpress PAK1, tamoxifen sensitive. IPA-3, a specific small MW PAK1 inhibitor, sensitised cells to tamoxifen only when EBP1 was ectopically expressed. IPA had no effect on tamoxifen resistance in T47D cells in which EBP1 protein had been ablated by shRNA. The IPA-induced increase in tamoxifen sensitivity was accompanied by a decrease in ErbB2 levels only in EBP1-overexpressing cells.
conclusionThese studies suggest that phosphorylation of EBP1 may be one mechanism of PAK1-induced hormone resistance and that PAK1 inhibitors may be useful in cells in which EBP1 is overexpressed.
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