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

• Published in: Oncogene Vol. 15; no. 12; pp. 1385 - 1394
• Main Authors: SCHAEFER, G, FITZPATRICK, V. D, SLIWKOWSKI, M. X
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 18.09.1997; Nature Publishing Group
• Subjects: Alternative Splicing; Amino Acid Sequence; Autocrine signalling; Base Sequence; Biological and medical sciences; Breast - metabolism; Breast cancer; Breast Neoplasms; Carrier Proteins - biosynthesis; Carrier Proteins - chemistry; Carrier Proteins - metabolism; Cell Division; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cloning, Molecular; Dimerization; ErbB-2 protein; ErbB-3 protein; Escherichia coli; Female; Fundamental and applied biological sciences. Psychology; Fusion protein; Growth factors; Growth Substances - biosynthesis; Heregulin; Humans; Hydrophobicity; Immunoglobulin G; Mesenchyme; Molecular and cellular biology; Molecular Sequence Data; Monoclonal antibodies; mRNA; Neuregulin; Neuregulin-1; Neurons - metabolism; Organ Specificity; Proto-Oncogene Proteins - metabolism; Receptor, Epidermal Growth Factor - metabolism; Receptor, ErbB-2 - metabolism; Receptor, ErbB-3; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - metabolism; Signal transduction; Small intestine; Transcription, Genetic; Tumor Cells, Cultured; Human; Cell proliferation; Alternative splicing; Molecular form; Nucleotide sequence; Tissue specificity; Molecular interaction; Gene expression; Mammary gland diseases; Cell line; Gene; Domain structure; Tumor; Mammary gland; Growth factor; Biological receptor
• ISSN: 0950-9232; 1476-5594
• 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.