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.
Highlights
Breast cancer is the most common cancer worldwide and the second most frequent cancer mortality in females [1]. 70% of all breast cancers are estrogen receptor α (ERα) positive, where ERα constitutes a driving force for breast cancer progression [2]
We found that high PAK4 expression was associated with poor disease-specific survival among the 915 Metabric ERα positive endocrine therapytreated patients in a univariable model (Figure 1A, HR = 1.34; 95% CI: 1.03–1.74)
One possible mechanism for the ERα Ser305 phosphorylation in tamoxifen resistance is an altered orientation between ERα and its coactivator SRC-1, which elevates the ERα transcription activity in the presence of tamoxifen [47, 48]
Summary
Breast cancer is the most common cancer worldwide and the second most frequent cancer mortality in females [1]. 70% of all breast cancers are estrogen receptor α (ERα) positive, where ERα constitutes a driving force for breast cancer progression [2]. 70% of all breast cancers are estrogen receptor α (ERα) positive, where ERα constitutes a driving force for breast cancer progression [2]. ERα exerts its functions through binding to estrogen responsive elements (EREs) or by indirect binding to DNA through other transcription factors, which subsequently induces the expression of target genes [3]. ERα positive breast cancer patients often benefit from ERα antagonist treatment. Tamoxifen is the most commonly used ERα antagonist in the clinic. Tamoxifen largely improves breast cancer patient survival, the development of tamoxifen-resistance is common. Post-translational modifications of ERα, such as phosphorylations, may play important roles in regulating estrogen signaling thereby overcoming tamoxifen responsiveness [6]
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