Prolyl isomerase Pin4 impacts estrogen receptor transactivation by enhancing phosphorylation and consequently promotes the proliferation of breast cancer cells

Breast cancer is the most common tumor in women, and approximately 70 % of cases are diagnosed to be estrogen receptor α (ERα)-positive. Estradiol (E2)-ERα signaling is undoubtedly involved in the development of breast cancer, and the upregulation of this pathway is linked to tamoxifen resistance. However, ERα regulation is complex, and the underlying mechanisms have not been comprehensively elucidated. Pin4 is a prolyl isomerase that promotes cis-trans isomerization of proline residues. Although its role remains unclear, an analysis of public databases reveals that Pin4 expression in breast cancer tissues is higher than that in normal tissues. Here, we reveal that Pin4 regulates ERα transcriptional activity and is essential for the proliferation of ERα-positive breast cancer cells. In MCF7 and T47D cells, Pin4 knockdown drastically decreased cell proliferation by inducing cell cycle arrest. In addition, the silencing of Pin4 impaired the expression of E2-induced genes, including E2F1. We also found that Pin4 interacted with ERα and affected its transcriptional activity by promoting phosphorylation at Ser167, which was involved in the recruitment of steroid receptor coactivator-3 (SRC-3) into ERα. Importantly, the silence of Pin4 gene in T47D cells attenuated the interaction between SRC-3 and ERα. Collectively, the study findings show that Pin4 is a critical factor in the development of ERα-positive breast cancers and the identification of Pin4 inhibitors could be a promising therapeutic strategy.