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.
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.
Wang
X Z
XZ
Department of Medicine, Skirball Institute of Biomolecular Medicine, Kaplan Cancer Center, NYU Medical Center, New York, NY 10016, USA.
Jolicoeur
E M
EM
Conte
N
N
Chaffanet
M
M
Zhang
Y
Y
Mozziconacci
M J
MJ
Feiner
H
H
Birnbaum
D
D
Pébusque
M J
MJ
Ron
D
D
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics* / Q000648:ultrastructure; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics* / Q000648:ultrastructure; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008565:Membrane Proteins; D020890:Neuregulin-1 / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology; D015398:Signal Transduction; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D008565:Membrane Proteins; D020890:Neuregulin-1; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D018719:Erb-b2 Receptor Tyrosine Kinases; C113761:Tenm4 protein, mouse; C108697:gamma-heregulin