Dexamethasone enhances the lung metastasis of breast cancer via a PI3K-SGK1-CTGF pathway

Dexamethasone (Dex), as a pretreatment agent, is widely used to attenuate the side effects of chemotherapy in breast cancer treatment. However, whether and how Dex affects breast cancer metastasis remain to be furtherly understood. In this study, we established several mouse breast cancer metastatic models to study the effect of Dex in vitro and in vivo. Transwell, Western Blot and RNA interference were applied to study the molecular mechanism of Dex in promoting breast cancer cell migration. Meanwhile, the effect of Dex on lung metastasis of breast cancer in Dex combined with PTX chemotherapy was discussed. Our results confirmed that Dex could promote breast cancer cell metastasis both in vitro and in vivo. Mechanistic studies revealed that this pro-metastatic effect of Dex was mediated by the GR-PI3K-SGK1-CTGF pathway in tumor cells. Ligation of Dex and glucocorticoid receptor (GR) on tumor cells activated the PI3K signaling pathway and upregulated serum glucocorticoid-inducible kinase 1 (SGK1) expression, and then increased the expression of connective tissue growth factor (CTGF) through Nedd4l-Smad2. Moreover, Dex was the leading factor for lung metastasis in a standard regimen for breast cancer treatment with paclitaxel and Dex. Importantly, targeting SGK1 with the inhibitor GSK650394 remarkably reduced lung metastasis in this regimen. Our present data provide new insights into Dex-induced breast cancer metastasis and indicate that SGK1 could be a candidate target for the treatment of breast cancer metastasis.