Résumé
The metastatic process requires changes in tumor celladhesion proerties, cell motility and remodeling of the extracellularmatrix. The erbB2 protooncogene is overexpressed in approximately 30percent of breast cancers and is a major prognostic parameter whenpresent in invasive disease. However, it is expressed more often innon-invasive tumors, where it has no prognostic significance, thus itsrole in promoting metastatic tumor progression is not clear. A ligand forthe erbB2 receptor has not yet been identified but it can be activated byheterodimerization with heregulin (HRG)-stimulated erbB3 and erbB4receptors. The HRGs are a family of polypeptide growth factors that havebeen shown to play a role in embryogenesis, tumor formation and growthand differentiation of breast cancer cells. The erbB3 and erbB4 receptorsare involved in transregulation of erbB2 signaling, however theirrespective contributions to the progression of breast cancer have not yetbeen determined. The work presented here suggests additional biologicalroles for HRG including regulation of the actin cytoskeleton andinduction of motility and invasion in breast cancer cells. HRG-expressingbreast cancer cell lines are characterized by low erbB receptor levelsand a high invasive and metastatic index, while those which overexpresserbB2 demonstrate minimal invasive potential in vitro and arenon-tumorigenic in vivo. Treatment of the highly tumorigenic andmetastatic HRG-expressing breast cancer cell line MDA-MB-231 with anHRG-neutralizing antibody significantly inhibited proliferation inculture and motility in the Boyden chamber assay. Addition of exogenousHRG ligand to non-invasive erbB2 overexpressing cells (SKBr-3) at lowconcentrations (0.2ng/ml) induced formation of pseudopodia, enhancedphagocytic activity and increased chemomigration and invasion in theBoyden chamber assay. The specificity of the chemomigration response toHRG is demonstrated by inhibition with the anti-HRG neutralizingantibody. These results suggest that HRG can act either as an autocrineor paracrine ligand to promote the invasive behavior of breast cancercells in vitro or thus may enhance the metastatic process invivo.