Characteristics of EGFR family-mediated HRG signals in human ovarian cancer

The ability of the epidermal growth factor receptor (EGFR) family members, EGFR, HER2, HER3, and HER4, to form homo- and heterodimers after interactio n with different ligands expands the signal diversity of these proteins. We investigated their mechanism of activation by exogenous EGF and heregulin (HRG) in human ovarian carcinoma cell lines which express different amounts and combinations of the four receptors. Consistently the predominant inter action after EGF treatment was between EGFR and HER2, whereas activation of HER3 and HER4 depended on the relative abundance of the four receptors in the cells. Remarkably HER3 activation by HRG could occurs independent of HE R2, and in one cell line almost no HER4 activation by HRG was detected desp ite high levels expression. Both EGF and HRG induced activation of mitogen- activated protein kinase (MAPK), but the time course of MAPK activation dif fered depending on the hetero-dimers induced. EGF and HRG mediated cell gro wth through the EGFR/HER2 heterodimer and HER4, respectively, but not throu gh HER3 when it was the only HRG receptor expressed and phosphorylated in t he cells. These findings reveal a distinct pattern of HRG induced EGFR fami ly interaction in ovarian cancer that is distinct from that described in hu man breast cancer. Moreover EGF and HRG can exert distinct biological funct ions depending on the receptor complexes induced in a given ovarian cancer cell line. (C) 1999 Wiley-Liss, Inc.