ER-α36 mediates cisplatin resistance in breast cancer cells through EGFR/HER-2/ERK signaling pathway

Background: ER-alpha 36, a novel ER-alpha 66 variant, has been demonstrated to promote tamoxifen resistance in breast cancer cells. However, the role and mechanisms of ER-alpha 36 in cisplatin resistance of breast cancer cells remain unclear. This study investigates the expression and role of ER-alpha 36 in cisplatin resistance of breast cancer cells and elucidates its underlying mechanisms. Methods: The expression of ER-alpha 36 and the proteins involved in nongenomic estrogen signaling was evaluated by western blot analysis. Cisplatin sensitivity was explored by CCK-8 assay, monolayer colony formation assay and apoptosis assays, respectively. ER-alpha 36 siRNAs/shRNAs and overexpression vector were transfected into cells to down-regulate or up-regulate ER-alpha 36 expression. Loss-and gain-of function assays were performed to investigate the role of ER-alpha 36 in cisplatin sensitivity. The interaction between ER-alpha 36 and EGFR/HER-2 were detected using CoIP. A mouse xenograft model of breast cancer was established to verify the role of ER-alpha 36 in vivo. Results: ER-alpha 36 is expressed at higher levels in cisplatin-resistant breast cancer cells compared to cisplatin sensitive cells. Cisplatin induced up-regulation of ER-alpha 36 in a dose-dependent manner in breast cancer cells. Overexpression of ER-alpha 36 leaded to cell resistant to cisplatin and knockdown of ER-alpha 36 in cisplatin-resistant breast cancer cells restored cisplatin sensitivity. The up-regulation of ER-alpha 36 resulted in increased activation of nongenomic estrogen signaling, which was responsible for cisplatin resistance. Disruption of ER-alpha 36-mediated nongenomic estrogen signaling with kinase inhibitors significantly inhibited cisplatin-induced expression of ER-alpha 36 and increased cisplatin sensitivity. The in vivo experiment also confirmed that up-regulation of ER-alpha 36 attenuated cisplatin sensitivity in a mouse xenograft model of breast cancer. Conclusions: The results for the first time demonstrated that ER-alpha 36 mediates cisplatin resistance in breast cancer cells through nongenomic estrogen signaling, suggesting that ER-alpha 36 may serve as a novel target for cisplatin resistance and a potential indicator of cisplatin sensitivity in breast cancer treatment.