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MBC in Press, published online ahead of print November 17, 2004
Mol. Biol. Cell 10.1091/mbc.E04-07-0567

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Submitted on July 7, 2004
Revised on October 12, 2004
Accepted on October 14, 2004

HGF Converts ErbB2/Neu Epithelial Morphogenesis to Cell Invasion

Hanane Khoury,*{dagger} Monica A. Naujokas,{ddagger} Dongmei Zuo,{ddagger} Veena Sangwan,*{ddagger} Melanie M. Frigault,*{dagger} Stephanie Petkiewicz,*{ddagger} David L. Dankort,{sect} William J. Muller,*{dagger} and Morag Park*{dagger}{ddagger}||¶

*Molecular Oncology Group, McGill University Health Center and Departments of {dagger}Biochemistry, {ddagger}Medicine, and ||Oncology, McGill University, Montreal, Quebec, Canada H3A 1A1; {sect}Cancer Research Institute, University of California, San Francisco/Mt. Zion Comprehensive Cancer Center, San Francisco, CA 94143-0128

Monitoring Editor: Anthony Pawson

Activation of the Hepatocyte Growth Factor receptor, Met, induces a morphogenic response and stimulates the formation of branching tubules by Madin-Darby Canine Kidney epithelial cells in three-dimensional cultures. A constitutively activated ErbB2/Neu receptor, (NeuNT), promotes a similar invasive morphogenic program in MDCK cells. Because both receptors are expressed in breast epithelia, are associated with poor prognosis and HGF is expressed in stroma, we examined the consequence of cooperation between these signals. We show that HGF disrupts NeuNT-induced epithelial morphogenesis, stimulating the breakdown of cell-cell junctions, dispersal and invasion of single cells. This correlates with a decrease in junctional proteins claudin-1 and E-cadherin, in addition to the internalization of the tight junction protein, Z0-1. HGF-induced invasion of NT-expressing cells is abrogated by pretreatment with a pharmacological inhibitor of the MEK pathway, which restores E-cadherin and ZO-1 at cell-cell junctions, establishing the involvement of MEK-dependent pathways in this process. These results demonstrate that physiological signals downstream from the HGF/Met receptor synergize with ErbB2/Neu to enhance the malignant phenotype, promoting the breakdown of cell-cell junctions and enhanced cell invasion. This is particularly important for cancers where ErbB2/Neu is overexpressed and HGF is a physiological growth factor found in the stroma.

Corresponding author. E-mail: morag.park{at}mcgill.ca




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