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 (ER?) is highly expressed in most breast cancers. Consequently, ER? modulators, such as tamoxifen, are successful in breast cancer treatment, although tamoxifen resistance is commonly observed. While tamoxifen resistance may be caused by altered ER? signaling, the molecular mechanisms regulating ER? 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 ER? bound to the PAK4 gene, thereby promoting PAK4 expression, while PAK4 in turn stabilized the ER? protein, activated ER? transcriptional activity and ER? target gene expression. Further, PAK4 phosphorylated ER?-Ser305, a phosphorylation event needed for the PAK4 activation of ER?-dependent transcription. In conclusion, PAK4 may be a suitable target for perturbing ER? signaling and tamoxifen resistance in breast cancer patients.

SUBMITTER: Zhuang T 

PROVIDER: S-EPMC4791272 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature