Activated-PAK4 predicts worse prognosis in breast cancer and promotes tumorigenesis through activation of PI3K/AKT signaling

Abstract

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.

PAK4 Pathway as a Potential Therapeutic Target in Pancreatic Cancer

“…These findings echo the results from other studies in breast and ovarian cancer [16]. There has been limited data in PDAC, although one small retrospective study surprisingly demonstrated that lower levels of PAK4 expression was associated with worse survival and tumor characteristics [17].…”

PAK4 regulates stemness and progression in endocrine resistant ER-positive metastatic breast cancer

“…In most adult tissues, PAK4 expression is low. However, its overexpression has not only been associated with oncogenic transformation [29,30], but also with disease stage in breast clinical specimens [31][32][33]. We found that PAK1/4-driven CSC activity increased as the disease progressed in sequential metastatic samples taken from 2 ER+ breast cancer patients.…”

“…Data supporting a role in breast cancer include oncogenic transformation of immortalised mouse mammary epithelial cells by PAK4 overexpression and PAK4 RNAi reversing the malignant phenotype of MDAMB231 breast cancer cells [29,30]. Moreover, 3 independent studies on the expression of PAK4 in breast clinical specimens at different disease stages showed that high protein levels correlate with larger tumour size, lymph node involvement and invasive disease [31][32][33]. Furthermore, PAK4 expression associates with poor clinical outcome in tamoxifen-treated patients and was demonstrated to positively regulating ER transcriptional activity in an endocrine resistant breast cancer cell line [34].…”

Normal mammary gland development after MMTV-Cre mediated conditional PAK4 gene depletion

“…PAK4 is involved in a variety of cytoskeletal regulation such as promoting filopodia formation, dissolution of stress fibers, controlling actin polymerization and depolymerization as well as focal adhesion turnover [19][20][21][22][23][24][25] . Consistently, PAK4 overexpression is correlated with poor patient outcome in breast cancer patients, and its overexpression in breast cancer cell lines was shown to increase cell survival, anchorage-independent growth, cell migration and invasion [26][27][28][29][30] . PAK4 also plays an essential role during embryonic development, as complete depletion of PAK4 in mice caused embryonic lethality with severe defects in the heart, brain, and vasculature of the animals; however, its role in mammary gland development has not been investigated [31][32][33] .…”