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

Abstract

g-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. g-heregulin has been found to be expressed in the culture supernatant of MDA-MB-175, a breast carcinoma cell line. g-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 g-heregulin is identical to the N-terminus of DOC4, a product of a recently identi®ed CHOPdependent stress-induced gene. Human DOC4 and the heregulin-encoding genes map to di erent 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, gheregulin is a product of a mutant fusion gene and not a bona ®de 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.

γ-Heregulin has no biological significance in primary breast cancer

“…Our results show that the t(8;11)(p12;q13) translocation is not present in a large series of Spanish women with breast cancer and confirm previous reports that suggest that this translocation is a particularity of the MDA-MB-175 cell line and not a recurrent event (Wang et al, 1999;Adélaïde et al, 2000) indicating that g-heregulin is not relevant in the development of breast cancer.…”

“…Moreover, NRG-1 synthesised by the mesenchyme has been implicated in mammary development (Carraway et al, 1997), and it has been demonstrated that NRG-1 induces proliferation or differentiation of various mammary tumour cell lines, initiates programmed cell death and induces cell differentiation in breast tumours (Ram et al, 1995;Weinstein et al, 1998;Le et al, 2000). Recently, it has been identified in MDA-MB-175, a breast carcinoma cell line that shows elevated levels of HER-2 (Lewis et al, 1993), a translocation between chromosomes 8p12-21 and 11q13 that leads to the fusion of NRG-1 and DOC4 genes (Schaefer et al, 1997;Liu et al, 1999;Wang et al, 1999;Adélaïde et al, 2000). This translocation generates a new chimeric transcript that codes for a new isoform of the neuregulin family, denominated g-heregulin (g-HRG), that acts as an autocrine growth factor in the breast cancer cell line MDA-MB-175 (Schaefer et al, 1997).…”

High-resolution analysis of chromosome rearrangements on 8p in breast, colon and pancreatic cancer reveals a complex pattern of loss, gain and translocation

“…MDA-MB-175 has a translocation of 8p12 at NRG1 that creates a fusion with the DOC4 gene on chromosome 11 (Wang et al, 1999;Liu et al, 1999;Adelaide et al, 2003). The fragment containing the junction is amplified (Figure 3).…”

“…NRG1 encodes the heregulins/neuregulin 1 family of ligands, which bind to ErbB2, 3 and 4. Our working hypothesis is that the translocations result in aberrant expression of normal or modified heregulins, which act in an autocrine loop on the cancer cells, as in at least one of the cell lines, MDA-MB-175, the translocation results in fusion of NRG1 and secretion of a fusion protein with soluble heregulin-like activity (Schaefer et al, 1997;Liu et al, 1999;Wang et al, 1999). We have subsequently shown that breakpoints in NRG1 are present in about 6% of uncultured breast tumours (Huang et al, 2004 also supported by Prentice et al, 2005).…”

Multicolour-banding fluorescence in situ hybridisation (mbanding-FISH) to identify recurrent chromosomal alterations in breast tumour cell lines

“…For other amplification regions, such as the 8p12 and 20q13 regions, and for deletions, the identity of the cancer genes remains uncertain. The characterisation of translocations has provided additional cancer gene candidates, such as FHIT (Popovici et al, 2002), NTRK3 and ETV6 (Tognon et al, 2002; our unpublished observations), BCAS (Bärlund et al, 2002) and NRG1 (Wang et al, 1999;Adélaïde et al, 2003;Huang et al, 2004) genes. Given the number of recurrent chromosomal breaks observed in breast cancer (http://cgap.nci.nih.gov/Chromosomes/ RecurrentAberrations), this line of research might become more fruitful than the search for deletions through loss of heterozygosity data, which has been rather disappointing (Devilee et al, 2001).…”