Research Papers:

p21-activated kinase group II small compound inhibitor GNE-2861 perturbs estrogen receptor alpha signaling and restores tamoxifen-sensitivity in breast cancer cells

Ting Zhuang, Jian Zhu, Zhilun Li, Julie Lorent, Chunyan Zhao, Karin Dahlman-Wright and Staffan Strömblad _

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Oncotarget. 2015; 6:43853-43868. https://doi.org/10.18632/oncotarget.6081

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Ting Zhuang1,*, Jian Zhu1,*, Zhilun Li1, Julie Lorent2, Chunyan Zhao1, Karin Dahlman-Wright1,3, Staffan Strömblad1

1Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge, Sweden

2Department of Oncology and Pathology, Karolinska Institutet, Solna, Sweden

3Science for Life Laboratory (SciLifeLab), Karolinska Institutet, Solna, Sweden

*These authors have contributed equally to this work

Correspondence to:

Staffan Strömblad, e-mail: [email protected]

Keywords: PAK4, ERα, tamoxifen resistance, phosphorylation, small molecule inhibitor

Received: July 07, 2015     Accepted: October 26, 2015     Published: November 06, 2015


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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