Phosphatidylethanolamine-binding protein 4 is associated with breast cancer metastasis through Src-mediated Akt tyrosine phosphorylation.

Abstract

Metastasis is responsible for more than 90% of the mortality observed among patients with breast cancer. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is a novel member of the PEBP family and functions as an anti-apoptotic molecule. Here, we found that the metastatic MDA-MB-231 breast cancer cells expressed much higher levels of hPEBP4 than the nonmetastatic MCF-7 breast cancer cells and that the expression levels of hPEBP4 were positively correlated with the metastasis of clinical breast cancer. The hPEBP4 overexpression in the MDA-MB-231 cells significantly promoted cell invasion in vitro and increased the development of lymph node metastasis in vivo. Conversely, the silencing of hPEBP4 suppressed the cell-invasive ability both in vitro and in vivo. Further investigation showed that hPEBP4 promoted the expression or activity of the metastasis-related proteinases MMP (matrix metalloproteinase) 2, MMP9 and MMP13. This hPEBP4-potentiated cell invasion and MMP expression is due to an increase in Akt activation. Knockdown of Akt restored hPEBP4-induced breast tumor metastasis in the hPEBP4-MDA-MB-231 xenograft mouse model. Moreover, we found that hPEBP4 functioned as a scaffolding molecule and enhanced the association of Akt with Src to promote Akt tyrosine phosphorylation, a prerequisite for the full activation of Akt, in a phosphatidylethanolamine-binding domain-dependent manner. Given the present information about human breast cancer, these functional data from cell culture and animal studies suggest that, in human breast cancer hPEBP4 is a novel and clinically relevant metastasis accelerator gene and may be a new diagnostic marker and therapeutic target for breast cancer metastasis.

• Authors: H Li, F Huang, L Fan, Y Jiang, X Wang, J Li, Q Wang, H Pan, J Sun, X Cao, X Wang
• Journal: Oncogene (Oncogene) Vol. 33 Issue 37 Pg. 4589-98 (Sep 11 2014) ISSN: 1476-5594 [Electronic] England
• PMID: 24276246 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• PE-binding protein 4, human
• Phosphatidylethanolamine Binding Protein
• Tyrosine
• src-Family Kinases
• Proto-Oncogene Proteins c-akt
• MMP13 protein, human
• Matrix Metalloproteinase 13
• MMP9 protein, human
• Matrix Metalloproteinase 9

Topics

• Animals
• Breast Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• MCF-7 Cells
• Matrix Metalloproteinase 13 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mice, Nude
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Neoplasm Transplantation
• Phosphatidylethanolamine Binding Protein (metabolism)
• Phosphorylation
• Protein Structure, Tertiary
• Proto-Oncogene Proteins c-akt (metabolism)
• Tissue Array Analysis
• Tyrosine (chemistry)
• src-Family Kinases (metabolism)