MST4: A Potential Oncogene and Therapeutic Target in Breast Cancer

Abstract

The mammalian STE 20-like protein kinase 4 (MST4) gene is highly expressed in several cancer types, but little is known about the role of MST4 in breast cancer, and the function of MST4 during epithelial-mesenchymal transition (EMT) has not been fully elucidated. Here we report that overexpression of MST4 in breast cancer results in enhanced cell growth, migration, and invasion, whereas inhibition of MST4 expression significantly attenuates these properties. Further study shows that MST4 promotes EMT by activating Akt and its downstream signaling molecules such as E-cadherin/N-cadherin, Snail, and Slug. MST4 also activates AKT and its downstream pro-survival pathway. Furthermore, by analyzing breast cancer patient tissue microarray and silicon datasets, we found that MST4 expression is much higher in breast tumor tissue compared to normal tissue, and significantly correlates with cancer stage, lymph node metastasis and a poor overall survival rate (p < 0.05). Taken together, our findings demonstrate the oncogenic potential of MST4 in breast cancer, highlighting its role in cancer cell proliferation, migration/invasion, survival, and EMT, suggesting a possibility that MST4 may serve as a novel therapeutic target for breast cancer.

MST4 promotes proliferation, invasion, and metastasis of gastric cancer by enhancing autophagy

“…Recurrence after radical gastrectomy is the main obstacle to improve the overall survival of GC patients, but its molecular mechanism has not been well understood until now. MST4 promotes proliferation and migration of various cancer cells via different mechanisms [ 26 , 30 , 31 ]. Arora et al demonstrated that MST4 as a oncogene enhances cell growth and migration by promoting EMT via activating Akt in breast cancer [ 26 ].…”

“…MST4 promotes proliferation and migration of various cancer cells via different mechanisms [ 26 , 30 , 31 ]. Arora et al demonstrated that MST4 as a oncogene enhances cell growth and migration by promoting EMT via activating Akt in breast cancer [ 26 ]. Moreover, MST4 directly phosphorylates β-catenin to promote the tumor cell proliferation and is associated with a poor prognosis of CRC [ 30 ].…”

“…MST4 also promotes tumor cell migration and metastasis by activating the p-ERK signaling pathway and interacting with FAM40A, a STRIPAK element [ 23 , 24 ]. Overexpression of MST4 is strongly related to poor prognoses of several carcinomas including hepatocellular carcinoma, breast cancer, choriocarcinoma, and prostate cancer [ [25] , [26] , [27] ]. However, there is no consensus on the function of MST4 in GC.…”

STE20‐type kinases MST3 and MST4 promote the progression of hepatocellular carcinoma: Evidence from human cell culture and expression profiling of liver biopsies

“…hepatocellular carcinoma, hepatocellular lipid droplets, MST3, MST4, nonalcoholic steatohepatitis, STE20-type kinases colorectal, prostate, and breast cancer as well as glioblastoma. [18][19][20][21][22][23][24][25][26] MST3 and MST4 are also implicated in the pathology of endothelial malformations, [27][28][29] in the regulation of neuronal function, [30][31][32] and in immune responses. 27,33,34 In this study, we focused on determining the relevance of STE20 kinases MST3 and MST4 in human HCC, and on investigating the possible synergies between these two proteins.…”

“…Conversely, a low MST4 abundance has also been reported to associate with the progression of HCC and poor patient prognosis, and the functional inactivation of MST4 was found to increase proliferation, motility, and invasion of human HCC cells in vitro and to facilitate intrahepatic metastatic potential in vivo 16,17 . Notably, MST3 and MST4 have previously been described to control tumorigenesis in gastric, pancreatic, colorectal, prostate, and breast cancer as well as glioblastoma 18–26 . MST3 and MST4 are also implicated in the pathology of endothelial malformations, 27–29 in the regulation of neuronal function, 30–32 and in immune responses 27,33,34 …”