Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis
Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis
Cancer Cell. 6, 459-469 (2004)
Speaker : 翁子玉 Time : 9/28/2005 14:00~15:00
Commentator : 周楠華醫師 Place : Room 601
Abstract:
HER2 is overexpresssed in about 30% of breast and other cancers. Its role in breast cancer has been widely studied1, however, the mechanism by which HER2 enhances metastasis is not completely understood, especially to the lung. Recently, it is suggested that SDF1-α and its receptor CXCR4 are involved in breast cancer metastasis2. The author hypothesized that CXCR4 plays a role in HER2-mediated metastasis. First, they found that HER2 is able to increase CXCR4 expression in HER2 stably transfectants and PI3K/Akt/mTor pathway may attribute in this phenomenon. In vitro studies also showed that SDF1-α and CXCR4 contributes to HER2-driven invasion, migration, and adhesion activities. Besides, stimulation of SDF1-α can degrade CXCR43. The author further investigated whether HER2 overexpression might prevent its degradation. By the pulse-chase assay and immunoprecipitation, they found that HER2 inhibits ligand-induced CXCR4 ubiquitination and subsequently prevents CXCR4 degradation, and an ubiquitin ligase AIP44 is involved in this process. Next, by using CXCR4 siRNA, they proved that CXCR4 is required for HER-induced lung metastasis in vivo. Finally, examination of the clinical specimens further supports the significant correlation of HER2 and CXCR4 expression and CXCR4 expression correlated with poor patient overall survival. Altogether, the authors provided a possible mechanism for HER2 mediated breast cancer metastasis and a functional link between HER2 and CXCR4 signaling pathway.
References:
1. Zhou, B.P et al. Dysregulation of cellular signaling by HER2/neu in breast cancer. Semin. Oncol. 30, 38–48 (2003).
2. Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 410, 50–56 (2001).
3. Marchese, A. et a. Agonist-promoted ubiquitination of the G protein-coupled receptor CXCR4 mediates lysosomal sorting. J. Biol. Chem. 276, 45509–45512 (2001).
4. Marchese, A. et a.l The E3 ubiquitin ligase AIP4 mediates ubiquitination and sorting of the G protein-coupled receptor CXCR4. Dev. Cell. 5, 709–722 (2003).