gamma-heregulin is the product of a chromosomal translocation fusing the DOC4 and HGL/NRG1 genes in the MDA-MB-175 breast cancer cell line

Oncogene. 1999 Oct 7;18(41):5718-21. doi: 10.1038/sj.onc.1202950.


gamma-heregulin is a recently described novel isoform of the heregulin/neuregulin class of EGF-like ligands that bind to and activate receptors of the ErbB family. Deregulated signaling through the heregulin-ErbB pathway is thought to be implicated in the development of a subset of human breast cancers. gamma-heregulin has been found to be expressed in the culture supernatant of MDA-MB-175, a breast carcinoma cell line. gamma-heregulin is characterized by the presence of a large N-terminal peptide extension that is not found in other heregulin isoforms. Here we report that this unique N-terminal extension of gamma-heregulin is identical to the N-terminus of DOC4, a product of a recently identified CHOP-dependent stress-induced gene. Human DOC4 and the heregulin-encoding genes map to different chromosomes and the MDA-MB-175 cell line contains a chromosomal translocation that leads to the fusion of DOC4 and HGL, on chromosomes 11 and 8, respectively. Thus, gamma-heregulin is a product of a mutant fusion gene and not a bona fide normal isoform. We speculate that the mutation may be selected for by virtue of its ability to activate ErbB signaling through the production of an autocrine ligand.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Carcinoma / genetics*
  • Carcinoma / pathology
  • Carrier Proteins / genetics*
  • Chromosomes, Human, Pair 11 / genetics*
  • Chromosomes, Human, Pair 11 / ultrastructure
  • Chromosomes, Human, Pair 8 / genetics*
  • Chromosomes, Human, Pair 8 / ultrastructure
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • In Situ Hybridization, Fluorescence
  • Membrane Proteins
  • Neuregulin-1 / genetics*
  • Nuclear Proteins / genetics*
  • Oncogene Proteins, Fusion / genetics*
  • Receptor, ErbB-2 / physiology
  • Signal Transduction
  • Translocation, Genetic*
  • Tumor Cells, Cultured


  • Carrier Proteins
  • Membrane Proteins
  • Neuregulin-1
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • Tenm4 protein, mouse
  • gamma-heregulin
  • Receptor, ErbB-2