title: 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.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: F
authors.initials: F
authors.lastname: Huang
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: L
authors.initials: L
authors.lastname: Fan
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.affiliation: School of Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: H
authors.initials: H
authors.lastname: Pan
authors.affiliation: School of Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Sun
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: X
authors.initials: X
authors.lastname: Cao
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D049488:Phosphatidylethanolamine Binding Protein / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D046888:Tissue Array Analysis; D014443:Tyrosine / Q000737:chemistry; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: C518018:PE-binding protein 4, human; D049488:Phosphatidylethanolamine Binding Protein; D014443:Tyrosine; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9