GAMMA-HEREGULIN - A NOVEL HEREGULIN ISOFORM THAT IS AN AUTOCRINE GROWTH-FACTOR FOR THE HUMAN BREAST-CANCER CELL-LINE, MDA-MB-175

A novel neuregulin isoform, termed gamma-HRG, was cloned and character ized from the human breast cancer cell line, MDA-MB-175. As observed w ith other neuregulins, gamma-HRG, is a product of alternative mRNA spl icing of the neuregulin gene, gamma-HRG contains the EGF-like and immu noglobulin-like domains that are commonly found in other family member s, but lacks a transmembrane and cytoplasmic region. The new isoform p ossesses a unique N-terminal region that includes a hydrophobic domain that may function as a secretion signal. A purified recombinant versi on of gamma-HRG competes for binding to soluble ErbB3- and ErbB4-IgG f usion proteins with affinities similar to those observed for rHRG beta 1(177-244). gamma-HRG has a wide distribution in mesenchymal or neuro nal tissues but in contrast to other neuregulins, it is not present in breast, lung, liver and small intestine. Expression of gamma-HRG with its cognate receptors, ErbB3 and ErbB2 suggested that the growth of t he MDA-MB-175 cell line might be a result of the stimulation of a grow th factor signaling pathway. Treatment of MDA-MB-175 cells with an ant i-ErbB2 monoclonal antibody that interferes with the ligand-dependent formation of ErbB2-ErbB3 heterodimer complexes shows a strong growth i nhibitory effect on this cell line. Moreover, incubation with a recept or-IgG fusion protein that neutralizes secreted gamma-HRG, also inhibi ts cell growth. These data suggest that the secretion of gamma-HRG by MDA-MB-175 cells leads to the formation of a constitutively active rec eptor complex and stimulates the growth of these cells in an autocrine manner.