Gamma-heregulin: a novel heregulin isoform that is an autocrine growth factor for the human breast cancer cell line, MDA-MB-175.

Abstract

A novel neuregulin isoform, termed gamma-HRG, was cloned and characterized from the human breast cancer cell line, MDA-MB-175. As observed with other neuregulins, gamma-HRG, is a product of alternative mRNA splicing of the neuregulin gene. Gamma-HRG contains the EGF-like and immunoglobulin-like domains that are commonly found in other family members, but lacks a transmembrane and cytoplasmic region. The new isoform possesses a unique N-terminal region that includes a hydrophobic domain that may function as a secretion signal. A purified recombinant version of gamma-HRG competes for binding to soluble ErbB3- and ErbB4-IgG fusion proteins with affinities similar to those observed for rHRGbeta1(177-244). Gamma-HRG has a wide distribution in mesenchymal or neuronal 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 the MDA-MB-175 cell line might be a result of the autocrine stimulation of a growth factor signaling pathway. Treatment of MDA-MB-175 cells with an anti-ErbB2 monoclonal antibody that interferes with the ligand-dependent formation of ErbB2-ErbB3 heterodimer complexes shows a strong growth inhibitory effect on this cell line. Moreover, incubation with a receptor-IgG fusion protein that neutralizes secreted gamma-HRG, also inhibits cell growth. These data suggest that the secretion of gamma-HRG by MDA-MB-175 cells leads to the formation of a constitutively active receptor complex and stimulates the growth of these cells in an autocrine manner.

• Authors: G Schaefer, V D Fitzpatrick, M X Sliwkowski
• Journal: Oncogene (Oncogene) Vol. 15 Issue 12 Pg. 1385-94 (Sep 18 1997) ISSN: 0950-9232 [Print] England
• PMID: 9333014 (Publication Type: Journal Article)

Chemical References

• Carrier Proteins
• Growth Substances
• Neuregulin-1
• Proto-Oncogene Proteins
• Recombinant Fusion Proteins
• gamma-heregulin
• ErbB Receptors
• Receptor, ErbB-2
• Receptor, ErbB-3

Topics

• Alternative Splicing
• Amino Acid Sequence
• Base Sequence
• Breast (metabolism)
• Breast Neoplasms
• Carrier Proteins (biosynthesis, chemistry, metabolism)
• Cell Division
• Cloning, Molecular
• Dimerization
• ErbB Receptors (metabolism)
• Escherichia coli
• Female
• Growth Substances (biosynthesis)
• Humans
• Molecular Sequence Data
• Neuregulin-1
• Neurons (metabolism)
• Organ Specificity
• Proto-Oncogene Proteins (metabolism)
• Receptor, ErbB-2 (metabolism)
• Receptor, ErbB-3
• Recombinant Fusion Proteins (biosynthesis, chemistry, metabolism)
• Transcription, Genetic
• Tumor Cells, Cultured