COOPERATIVE SIGNALING OF ERBB3 AND ERBB2 IN NEOPLASTIC TRANSFORMATIONAND HUMAN MAMMARY CARCINOMAS

In the present study we demonstrate that erbB-3 and erbB-2 cooperate i n neoplastic transformation. Under conditions in which neither gene al one induced transformation, they readily transformed NIH3T3 cells if c oexpressed. Furthermore, at high expression levels of ErbB2 which caus e transformation, ErbB3 enhanced focus formation by one order of magni tude. Synergy required an intact ErbB2 extracellular domain and tyrosi ne kinase activity. Cooperation between ErbB3 and ErbB2 involved heter odimerization and increased tyrosine phosphorylation of ErbB3. Signali ng by the heterodimer resulted in increased PI 3-kinase recruitment as web as quantitative and qualitative differences in substrate phosphor ylation. Evidence for signaling by an active ErbB3-ErbB2 heterodimer i n four mammary tumor cell lines indicated relevance of this mechanism for human neoplasia. Our detection of the NDF/heregulin transcript in NIH3T3 cells implicates an autocrine loop involving this ligand in sig naling by the ErbB3-ErbB2 heterodimer in the model system, whereas her egalin-independent mechanisms likely exist for cooperative signaling b y ErbB3 and ErhB2 chronically activated in some human mammary carcinom as.