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Mol Cancer Ther. 2010 Mar;9(3):606-16. doi: 10.1158/1535-7163.MCT-09-0560. Epub 2010 Feb 23.

The prolyl isomerase Pin1 enhances HER-2 expression and cellular transformation via its interaction with mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1.

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1
BK21 Project Team, College of Pharmacy, Chosun University, Gwangju, Republic of Korea.

Abstract

The HER-2 oncogene, a member of the erythroblastosis oncogene B (ERBB)-like oncogene family, has been shown to be amplified in many types of cancer, including breast cancer. However, the molecular mechanism of HER-2 overexpression is not completely understood. The phosphorylation of proteins on the serine or threonine residues that immediately precede proline (pSer/Thr-Pro) is specifically catalyzed by the prolyl isomerase Pin1 and is a key signaling mechanism in cell proliferation and transformation. Here, we found that Pin1 interacts with mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) protein kinase 1, resulting in the induction of HER-2 expression. Pin1(-/-) mouse embryonic fibroblasts exhibited a decrease in epidermal growth factor (EGF)-induced MEK1/2 phosphorylation compared with Pin1(+/+) mouse embryonic fibroblast. In addition, a knockdown of Pin1 resulted in the inhibition of MEK1/2 phosphorylation induced by EGF in MCF-7 cells. Furthermore, PD98059, a specific inhibitor of MEK1/2, and Juglone, a potent Pin1 inhibitor, markedly suppressed the expression of activator protein-2alpha and the HER-2 promoter activity induced by EGF or 12-O-tetradecanoylphorbol-13-acetate in MCF-7 cells. Importantly, these inhibitors inhibited the neoplastic cell transformation induced by EGF in Pin1-overexpressing JB6 Cl41 cells, which showed enhanced cellular formation compared with the control cells. Therefore, Juglone and PD98059 inhibited the colony formation of MCF-7 breast cancer cells in soft agar. These results indicate that Pin1 amplifies EGF signaling in breast cancer cells through its interaction with MEK1 and then enhances HER-2 expression, suggesting that Pin1 plays an important role in the overexpression of HER-2 through Pin1-MEK1-activator protein-2alpha signaling in breast cancer.

PMID:
20179161
DOI:
10.1158/1535-7163.MCT-09-0560
[Indexed for MEDLINE]
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