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Controlled Activation of ErbB1/ErbB2 Heterodimers Promote Invasion of Three-Dimensional Organized Epithelia in an ErbB1-Dependent Manner: Implications for Progression of ErbB2-Overexpressing Tumors

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York

Requests for reprints: Senthil K. Muthuswamy, Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724. Phone: 516-367-6975; Fax: 516-367-8461; E-mail: muthuswa{at}cshl.edu.

Receptor tyrosine kinases of the ErbB family are implicated in a number of cancers, including that of the breast. ErbB receptors are activated by ligand-induced formation of homodimers and heterodimers. Receptor heterodimerization is thought to play a critical role in breast cancers overexpressing multiple members of the ErbB family. Although coexpression of ErbB receptors is associated with poor patient prognosis, the mechanisms by which receptor heterodimerization regulates tumor progression are not clear, due in part to a lack of methods that allow controlled activation of specific receptor heterodimers in mammary epithelial cells. Here, we report an approach to activate ErbB1-ErbB2 heterodimers in a nontumorigenic breast epithelial cell line, MCF-10A, without interference from endogenous ErbB receptors. Using such a method, we show that whereas both ErbB2 homodimers and ErbB1-ErbB2 heterodimers were equally potent in activating the Ras/mitogen-activated protein kinase pathway, the heterodimers were more potent in activating the phosphoinositide 3'-kinase (PI3K) and phospholipase C1 pathways than ErbB2 homodimers. We combined the dimerization system with a three-dimensional cell culture approach to show that whereas both ErbB2 homodimers and ErbB1-ErbB2 heterodimers induced disruption of three-dimensional acini-like structures, only heterodimers promoted invasion of cells through extracellular matrix. The ability of heterodimers to induce invasion required the ErbB1 kinase activity and required activation of PI3K, Ras/mitogen-activated protein kinase, and phospholipase C1 signaling pathways. Thus, we have identified cell invasion as a heterodimer-specific biological outcome and suggest that coexpression of ErbB1 may critically regulate invasive progression of ErbB2-positive breast cancers. (Cancer Res 2006; 66(10): 5201-8)

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