title: p21-activated kinase group II small compound inhibitor GNE-2861 perturbs estrogen receptor alpha signaling and restores tamoxifen-sensitivity in breast cancer cells.
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.
authors.affiliation: Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhuang
authors.affiliation: Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Zhilun
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Solna, Sweden.
authors.forename: Julie
authors.initials: J
authors.lastname: Lorent
authors.affiliation: Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge, Sweden.|Science for Life Laboratory (SciLifeLab), Karolinska Institutet, Solna, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Dahlman-Wright
authors.affiliation: Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Staffan
authors.initials: S
authors.lastname: Strömblad
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D030541:Databases, Genetic; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D016133:Polymerase Chain Reaction; D011743:Pyrimidines / Q000494:pharmacology*; D034741:RNA, Small Interfering; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D013629:Tamoxifen / Q000494:pharmacology; D014162:Transfection; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: C587762:1-(2-(1-(2-aminopyrimidin-4-yl)-2-((2-methoxyethyl)amino)-1H-1,3-benzodiazol-6-yl)ethynyl)cyclohexan-1-ol; D001562:Benzimidazoles; C506487:ESR1 protein, human; D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D011743:Pyrimidines; D034741:RNA, Small Interfering; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; C116367:PAK4 protein, human; D054462:p21-Activated Kinases
keywords: ERα; PAK4; phosphorylation; small molecule inhibitor; tamoxifen resistance