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The Neuregulin Family of Genes and their Multiple Splice Variants in Breast Cancer

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Abstract

The neuregulin family consists of four genes, NRG1–4 which can each encode products containing a domain related to the epidermal growth factor family of ligands. Each gene is subject to complex control of transcription and to splicing of their mRNA product to give many variant proteins. These do not contain secretory sequences but some, through their transmembrane sequence, are routed via the Golgi where they are glycosylated, to the cell surface. Here they may be released by regulated proteolysis to act as soluble proteins which can interact and activate members of the EGF receptor family of receptor tyrosine kinases. Other splice variants do not encode transmembrane sequences and these are found either in the cytoplasm or, if they encode a nuclear localisation sequence, in distinct compartments in the nucleoplasm. It has been shown that the variants containing a full EGF domain can act as receptor agonists but the function of the cytoplasmic and nuclear products is unknown as yet. All four neuregulin genes are expressed and play an important role in mammary gland development. They are also expressed at elevated levels in some cases of ductal carcinoma in situ of the breast and breast cancer. They seem to be active in this setting and their presence may affect the efficacy of treatment with endocrine agents or with signal transduction inhibitors directed at the EGF receptor family members. Much remains to be learned however of their normal function and their influence on breast cancer development, progression and response to therapy.

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Abbreviations

EGF:

epidermal growth factor

TGF-α:

transforming growth factor alpha

HER:

human epidermal growth factor receptor

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Acknowledgments

We are grateful to Dr. Richard Williamson, Department of Biosciences, University of Kent, UK for creating the three dimensional representation shown in the supplementary figure.

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  1. Department of Biosciences, University of Kent, Canterbury, Kent, CT2 7NJ, UK

    Nandini V. L. Hayes & William J. Gullick

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Correspondence to William J. Gullick.

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Supplementary Figure 1

a The three dimensional structure of the EGF receptor (blue) in a complex with TGFα (green) (Garrett et al., Cell 110:763–773, 2002). b Same, but shown lacking the equivalent C-terminal residues absent in the γ class of neuregulin products. It can be seen that, if the structure could form, there would still be significant contacts between the ligand and both receptor domains (L1 and L2) (DOC 552 KB).

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Hayes, N.V.L., Gullick, W.J. The Neuregulin Family of Genes and their Multiple Splice Variants in Breast Cancer. J Mammary Gland Biol Neoplasia 13, 205–214 (2008). https://doi.org/10.1007/s10911-008-9078-4

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