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

Oncogene. 1997 Sep 18;15(12):1385-94. doi: 10.1038/sj.onc.1201317.


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.

MeSH terms

  • Alternative Splicing*
  • Amino Acid Sequence
  • Base Sequence
  • Breast / metabolism
  • Breast Neoplasms
  • Carrier Proteins / biosynthesis*
  • Carrier Proteins / chemistry
  • Carrier Proteins / 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
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Transcription, Genetic*
  • Tumor Cells, Cultured


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

Associated data

  • GENBANK/AF009227