THE ROLE OF ERBB2-SIGNAL TRANSDUCTION PATHWAYS IN HUMAN BREAST-CANCER

The erbB2 receptor is expressed at very high levels in nearly 30% of h uman breast cancer patients and plays an important role in the transfo rmation and the prognosis of breast cancer. While evidence accumulates to support the relationship between erbB2 overexpression and poor ove rall survival in human breast cancer, understanding of the biological consequence(s) of erbB2 overexpression remains elusive. Our recent dis covery, cloning, sequencing, and expression of the erbB2 ligand (gp30) has allowed us to identify a number of related but distinct biologica l endpoints which appear responsive to signal transduction through the erbB2 receptor. These endpoints of growth, invasiveness, and differen tiation have clear implications for the emergence, maintenance, and/or control of malignancy, and represent established endpoints in the ass essment of malignant progression in breast cancer. Studies in vitro ha ve shown that gp30 induces a biphasic growth effect (induction of grow th at low concentrations and inhibition of growth at high concentratio ns) on cells with erbB2 over-expression. Strikingly, we have recently observed that the erbB2 signalling pathway can be modulated by estroge n acting through the estrogen receptor (ER). Conversely, we observed t hat down regulation of erbB2 by estrogen can be blocked by gp30 acting through the erbB2 receptor. Clearly, mechanistic aspects of the erbB2 /ligand interaction need to be understood from a therapeutic standpoin t, and may furthermore provide additional insights into treatment syne rgy for particular patients. We think that these studies will facilita te the emergence of erbB2-targeted therapy.