How the overexpressed hPTTG1 gene promotes metastasis in breast cancer

AbstractHuman pituitary tumor-transforming gene (hPTTG1) is a human securin homolog. It functions as a mitosis regulator during cell cycle progression in normal cells. It is also an oncogenic transcription factor. Deletion of the PTTG1 gene or its overexpression causes chromosome instability, increasing the probability of tumor formation and metastasis. PTTG1 has been found to be overexpressed in most human carcinomas with metastatic grade and blastic leukemia. Thus, overexpressed PTTG1 is suspected to promote tumor metastasis. However, the mechanism by which overexpressed PTTG1 drives tumor cells into metastasis remains unclear, but it is assumed to occur through activation of its target genes involved in the metastasis processes. Among the PTTG1-activated genes, GEFH1 and CXCR2 were shown to be directly regulated by PTTG1. Molecular biological studies and examination of human tumor samples indicated that overexpressed PTTG1 promotes tumor metastasis through activation of GEFH1/RhoA signaling, resulting in remodeling of cytoskeletal dynamics, enhancing the invasiveness of cancer cells, and driving tumor cells toward metastasis in vivo. Overexpressed PTTG1 can also activate CXCR2, which usually induces senescence in cancer cells if the CXCR2/p21 senescence pathway is functional. However, in most malignant tumor cells in which the CXCR2/p21 senescence pathway is defective, these tumor cells escape senescence and move toward metastasis. In these cells, overexpressed PTTG1 directly activates CXCR2 and its ligands, interleukin-8 (IL-8), and Gro-α or indirectly activates nuclear factor-κB to activate IL-8 and Gro-α. These cytokines, in turn, recruit inflammatory cells to the tumor sites creating microenvironments that favor tumor metastasis. Thus, PTTG1-overexpressed cancer cells can use myriad pathways to execute metastasis. It is important to screen for inhibitors that can neutralize the functions of overexpressed PTTG1. These inhibitors could be significant in the therapeutic arsenal against metastatic cancers