TCRP1 induces tamoxifen resistance by promoting the activation of SGK1 in MCF-7 cells

Abstract

Tamoxifen is widely used as a highly effective drug for treating estrogen-receptor (ER) alpha-positive breast cancer. However, tamoxifen resistance developed during cancer treatment remains a significant challenge. Tongue cancer resistance-related protein1 (TCRP1), which is recognized as a novel drug target, is related to chemo-resistance in human cancers, moreover, it is often overexpressed in various cancer cells, such as in lung cancer, breast cancer, and tongue cancer. However, the effects of TCRP1 on tamoxifen-resistant breast cancer cells and tissues are far from clear. The present study revealed that TCRP1 induced tamoxifen resistance in breast cancer cells. Western blotting, quantitative real-time polymerase chain reaction (RT-PCR) and immunohistochemical staining were performed to detect the expression level of TCRP1 in vivo and in vitro between primary breast cancer tissues and tamoxifen-resistant breast cancer tissues. The data revealed that the expression of TCRP1 was upregulated in the tamoxifen-resistant breast cancer tissues and human breast cancer cell line, MCF-7. Further study revealed that knocking down TCRP1 inhibited the growth of MCF-7 cells with tamoxifen-resistance (MCF7-R cells) and induced cell apoptosis. Moreover, TCRP1 promoted serum- and glucocorticoid-inducible kinase 1 (SGK1) activation via phosphorylation of phosphoinositide-dependent kinase 1 (PDK1) in MCF7-R cells. In addition, it was also observed that knocking down TCRP1 inhibited tumorigenesis of MCF-7 cells in nude mice. In conclusion, these data indicated that TCRP1 could induce tamoxifen resistance by regulating the PDK1/SGK1 signaling pathway. Thus, TCRP1 could be explored as a promising candidate for treating tamoxifen-resistant breast cancer in the future.