MODULATION OF BREAST-CANCER PROGRESSION AND DIFFERENTIATION BY THE GP30 NEREGULIN/

In the last decade we have come to understand that the growth of cance r cells in general and of breast cancer in particular depends, in many cases, upon growth factors that will bind to and activate their recep tors. One of these growth factor receptors is the erbB-2 protein which plays an important role in the prognosis of breast cancer and is over expressed in nearly 30% of human breast cancer patients. While evidenc e accumulates to support the relationship between erbB-2 overexpressio n and poor overall survival in breast cancer, understanding of the bio logical consequence(s) of erbB-2 overexpression remains elusive. Our r ecent discovery of the gp30 has allowed us to identify a number of rel ated but distinct biological endpoints which appear responsive to sign al transduction through the erbB-2 receptor. These endpoints of growth , invasiveness, and differentiation have clear implications for the em ergence, maintenance and/or control of malignancy, and represent estab lished endpoints in the assessment of malignant progression in breast cancer. We have shown that gp30 induces a biphasic growth effect on ce lls with erbB-2 over-expression. We have recently determined the prote in sequence of gp30 and cloned its full length cDNA sequence. We have also cloned two additional forms to the ligand, that are believed to b e different isoforms. We are currently expressing the different forms in order to determine their biological effects. To elucidate the cellu lar mechanisms underlying cell growth inhibition by gp30, we tested th e effect of this ligand on cell growth and differentiation of the huma n breast cancer cells which overexpress erbB-2 and cells which express low-levels of this protooncogene. High concentrations of ligand induc ed differentiation of cells overexpressing erbB-2, as measured by inhi bition of cell growth, and increased synthesis of milk components, and modulation of E-cadherin and up-regulation of c-jun and c-fos. These findings indicate that ligand-induced growth inhibition in cells overe xpressing erbB-2 is associated with an apparent induction of different iation. The availability of gp30 derived synthetic peptides and its fu ll cDNAs provides tools necessary to acquire a better understanding of the mechanism of action of the this ligands and the erbB-2 receptor i n breast cancer.