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Biophys. J. BioFAST: First Published June 16, 2006. doi:10.1529/biophysj.106.088898
© 2006 by the Biophysical Society.

A more recent version of this article appeared on August 15, 2006.
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BIOPHYSICAL LETTERS

A high-throughput migration assay reveals HER2-mediated cell migration arising from increased directional persistence

Neil Kumar 1, Muhammad H Zaman 1, Hyung-Do Kim 1 and Douglas A Lauffenburger 1*

1 MIT

* To whom correspondence should be addressed. E-mail: lauffen{at}mit.edu.

Submitted on May 13, 2006
Revised on May 25, 2006
Accepted on 7 June 2006


  Abstract
Human epidermal growth factor receptor 2 (HER2) overexpression has been associated with increased invasiveness in mammalian breast cancer cell lines, but the effects of overexpression on key underlying cell migration properties such as translational speed and directional persistence are not understood. Moreover, the differential effect of HER2 activation through heterodimerization with epidermal growth factor receptor (EGFR) versus human epidermal growth factor receptor 3 (HER3) on cell speed and persistence has not been studied. To investigate these issues, we developed a high-throughput wound closure assay in which individual cell locomotion and wound closure kinetics were quantified in human mammary epithelial cells (HMECs) with varying levels of HER2 under epidermal growth factor (EGF) or heregulin (HRG, a HER3 ligand) stimulation. Increasing levels of HER2 elevated wound closure with closure kinetics dependent on ligand treatment. Cell speed increased with HER2 levels under EGF treatment, but decreased under HRG treatment. In contrast, directional persistence increased with HER2 levels under both ligand treatments. Increasing persistence quantitatively accounted for observed elevated wound closure, as measured by the effective diffusion of the cells. Taken together, the data show that the HER2 overexpression mediates cell migration through differential control of translational speed and directional persistence dependent on EGFR-HER2 versus HER2-HER3 heterodimerization. Observed consistent increases in persistence associated with HER2 overexpression indicate a prospective mechanism for invasiveness previously documented in HER2-overexpressing human breast tumors.

Key Words: EGF, ErbB, cancer, cell migration




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Copyright © 2006 by the Biophysical Society.