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Status |
Public on Dec 12, 2015 |
Title |
P21-activated kinase group II small compound inhibitor GNE-2861 perturbs estrogen receptor alpha signaling and restores tamoxifen-sensitivity in breast cancer cells |
Organism |
Homo sapiens |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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Summary |
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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Overall design |
MCF7 cells were serum-starved for 72h and then treated with E2 for 45 min.
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Contributor(s) |
Zhuang T, Zhu J, Li Z, Lorent J, Zhao C, Dahlman-Wright K, Strömblad S |
Citation(s) |
26554417 |
Submission date |
Sep 22, 2015 |
Last update date |
May 15, 2019 |
Contact name |
Karin Dahlman-Wright |
Organization name |
Karolinska Institutet
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Department |
Department of Biosciences and Nutrition
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Lab |
Medicinaren 25/Neo
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Street address |
Blickagången 16
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City |
Huddinge |
ZIP/Postal code |
14157 |
Country |
Sweden |
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Platforms (1) |
GPL9052 |
Illumina Genome Analyzer (Homo sapiens) |
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Samples (2) |
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Relations |
BioProject |
PRJNA296591 |
SRA |
SRP063987 |
Supplementary file |
Size |
Download |
File type/resource |
GSE73320_RAW.tar |
260.0 Kb |
(http)(custom) |
TAR (of BED) |
SRA Run Selector |
Raw data are available in SRA |
Processed data provided as supplementary file |
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