Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis

Yan M. Li, Yong Pan, Yongkun Wei, Xiaoyun Cheng, Binhua P. Zhou, Ming Tan, Xiaoyan Zhou, Weiya Xia, Gabriel N. Hortobagyi, Dihua Yu, Mien Chie Hung

Research output: Contribution to journalArticlepeer-review

472 Scopus citations

Abstract

The receptor tyrosine kinase HER2 enhances tumor metastasis; however, its role in homing to metastatic organs is poorly understood. The chemokine receptor CXCR4 has recently been shown to mediate the movement of malignant cancer cells to specific organs. Here, we show that HER2 enhances the expression of CXCR4, which is required for HER2-mediated invasion in vitro and lung metastasis in vivo. HER2 also inhibits ligand-induced CXCR4 degradation. Finally, a significant correlation between HER2 and CXCR4 expression was observed in human breast tumor tissues, and CXCR4 expression correlated with a poor overall survival rate in patients with breast cancer. These results provide a plausible mechanism for HER2-mediated breast tumor metastasis and establish a functional link between HER2 and CXCR4 signaling pathways.

Original languageEnglish
Pages (from-to)459-469
Number of pages11
JournalCancer Cell
Volume6
Issue number5
DOIs
StatePublished - Nov 2004

Bibliographical note

Funding Information:
This work was supported by NIH RO1 grants CA058880 and CA109311, PO1 CA099031, and the National Breast Cancer Research Foundation (M.-C.H.); DAMD 17-02-1-0694 (G.N.H.); MDACC Cancer Center Supporting Grant (CA16672); and a predoctoral fellowship from the US Army Breast Cancer Research Program, grant DAMD 17-02-1-0454 (Y.M.L.). We would like to thank Dr. Nelson L. Michael for CXCR4 plasmid; Dr. Benovic for HA-CXCR4 and FLAG-ubiquitin constructs; Dr. Tony Pawson for wild-type and catalytically inactive AIP4 plasmids; Dr. Jeng C. Cheng, Dr. Stephanie A. Miller, and the Department of Scientific Publications at the University of Texas M.D. Anderson Cancer Center for editing the manuscript; Bill Spohn for help with microscopy setup and image processing; Jean Wang for statistical assistance; Dr. Chin-Hsing Chen for performing mice tail vein injections; and Chu-Li Weng for preparing animal tissue.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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