Serum- and glucocorticoid-induced kinase3, SGK3, enhances tamoxifen-sensitivity in ER positive breast cancer cell by inhibiting tamoxifen-induced autophagy

Tamoxifen, an estrogen antagonist that has been universally used for the treatment of estrogen receptor (ER) positive breast cancer, long-time treatment of tamoxifen may bring patients the drug-resistance ability. So, find the novel mechanisms behind the drug-resistance and discover drug that sensitized tamoxifen is of importance. Serum- and glucocorticoid-induced kinase3, SGK3, belongs to the SGK family of AGC kinase and functions in parallel to AKT downstream of PI3K. Previous studies have shown that SGK3 may be the major kinase responsible for the progression of breast cancer (BC) patients. Autophagy is associated with a variety of pathological conditions including cancer and neurodegenerative diseases. Autophagy has been discovered in tamoxifen resistance, showing important cell survival mechanism causing therapy resistance, combined with autophagy inhibitors increased rate of inhibition to tamoxifen, acquired tamoxifen-resistant breast cancer cell line TAM-R showed higher pro-survival autophagy compared to the parental cells. However, the resistance of tamoxifen whether associated with SGK3 expression level is unknown, and the mechanism of action is also unclear. Here, our study revealed that TAM-R cell line showed a low expression level of SGK3, along with high autophagy compared with parental cell line. Further, our study revealed that overexpression of SGK3 can increase the sensitivity of tamoxifen. Mechanistically, SGK3 increased the sensitivity of tamoxifen is associated with inhibition of autophagy. In total, targeting SGK3 opened a novel strategy to interrupt autophagy and tamoxifen resistance in breast cancer.