Activated-PAK4 predicts worse prognosis in breast cancer and promotes tumorigenesis through activation of PI3K/AKT signaling
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Li-Fang He1,2,*, Hong-Wu Xu2,3,*, Min Chen2,*, Zhi-Rong Xian2, Xiao-Fen Wen2, Min-Na Chen2, Cai-Wen Du4, Wen-He Huang1, Jun-Dong Wu1, Guo-Jun Zhang1,2
1The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong, China
2Changjiang Scholar Laboratory, Shantou University Medical College, Shantou 515041, Guangdong, China
3Department of Neurosurgery, Second Affiliated Hospital of Shantou, University Medical College, Shantou 515031, Guangdong, China
4Department of Breast Medical Oncology, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong, China
*These authors contributed equally to this work
Guo-Jun Zhang, email: firstname.lastname@example.org
Keywords: p21-activated kinase 4 (PAK4), prognostic marker, breast cancer, PI3K, AKT
Received: July 07, 2015 Accepted: January 27, 2016 Published: February 17, 2016
The p21-activated kinase 4 (PAK4) is sufficient to transform noncancerous mammary epithelial cells and to form tumors in the mammary glands of mice. The accumulated information suggests that PAK4 might be an oncogenic protein in breast cancer. In this study, we sought to identify the role for PAK4 in breast cancer progression. Immunohistochemical study revealed that high PAK4 expression is associated with larger tumor size, lymph node metastasis, and advanced stage cancer in 93 invasive breast carcinoma patients. Moreover, high PAK4 expression was significantly associated with poor overall and disease-free survival. PAK4 remained an independent adverse prognosticator after univariate and multivariate analysis. Ectopic expression of wild-type PAK4 in MDA-MB-231 cells activated PI3K/AKT signaling and resulted in the enhancement of the cell proliferation, migration, and invasion, whereas PAK4-induced effects were blocked by the PAK4 kinase inhibitor PF- 3758309, PAK4 siRNAs or the PI3K inhibitor LY294002. Furthermore, a kinase-active PAK4 (S474E) strongly induced PI3K/AKT activation, and promoted proliferation, migration and invasion in breast cancer cells. A kinase-inactive PAK4 KD (K350A/K351A) did partially upregulate PI3K/AKT, and promoted invasive phenotype. Taken together, these findings suggest that PAK4-activated PI3K/AKT signaling is both kinase-dependent and -independent, which contributes to breast cancer progression. Thus, our results imply that dual inhibition of PAK4 and PI3K/AKT signaling might be a potential therapeutic approach for breast cancer therapy.
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