LAMININ ACTIVATES THE P185(HER2) ONCOPROTEIN AND MEDIATES GROWTH-INHIBITION OF BREAST-CARCINOMA CELLS

The interaction between laminin and the oncoprotein encoded by the c-e rbB-2 oncogene was studied in vitro and in vivo in human breast carcin omas. In vitro analysis of breast carcinoma cell Lines overexpressing p185(HER2) revealed that laminin, but not fibronectin, induced tyrosin e phosphorylation and down-modulation of oncoprotein membrane expressi on. Laminin also specifically inhibited growth of p185(HER2)-positive cell lines. No direct binding between the recombinant extracellular do main of p185(HER2) and laminin was found. Induction of oncoprotein dow n-modulation by anti-integrin antibodies and coprecipitation of the on coprotein with the beta 4 integrin subunit indicate that the interacti on between p185(HER2) and laminin occurs through integrin molecules. T he relevance of this in vitro observation was verified in vivo by anal ysing the prognostic value of p185(HER2) overexpression as a function of laminin production on archival paraffin-embedded sections of 887 pr imary breast tumours. The results revealed an association between p185 (HER2) overexpression and unfavourable prognosis in tumours negative f or laminin production, whereas in laminin-producing tumours, the oncop rotein overexpression was not associated with tumour aggressiveness.