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Gene Review

NRG4  -  neuregulin 4

Homo sapiens

Synonyms: HRG4, Pro-NRG4, Pro-neuregulin-4, membrane-bound isoform
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Disease relevance of NRG4

  • In this study we examined using immunohistochemical staining expression of NRG1alpha, NRG1beta, NRG2alpha, NRG2beta, NRG3 and NRG4 in sixty cases of pre-invasive ductal carcinoma in situ of the breast representing different degrees of differentiation [1].
  • NRG4 overexpression is associated with advanced-stage prostate cancer [2].

High impact information on NRG4

  • Consistent with specificity to ErbB-4, NRG-4 can displace an ErbB-4-bound NRG-1 and can activate signaling downstream of this receptor [3].
  • The predicted pro-NRG-4 is a transmembrane protein carrying a unique EGF-like motif and a short cytoplasmic domain [3].
  • Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase [3].
  • Expression of NRG-4 mRNA was detected in the adult pancreas and weakly in muscle; other tissues displayed no detectable NRG-4 mRNA [3].
  • A significantly lower mRNA expression level of HER3 (P=0.0003), HRG2alpha (P=0.0159), HRG2beta (P=0.0007) and HRG4 (P<0.0001) was observed in muscle-invasive (T2-T4) tumours as compared to superficial (Ta) tumours [4].

Associations of NRG4 with chemical compounds

  • In contrast, inhibition of tyrosine kinase activity of HER1 with 5 muM Iressa (a specific inhibitor of HER1) resulted in an increase in mRNA expression of HRG2alpha (2.5-fold) and HRG4 (1.5-fold) [5].

Other interactions of NRG4

  • High levels of expression of NRG2beta and NRG4 were associated with high-grade tumours (p</=0.005), NRG2beta staining was associated with tumour size >25 mm (p=0.005) while NRG3 nuclear staining was present more often in low-grade tumours (p=0.039) [1].
  • Here we characterize a fourth neuregulin, NRG-4, that acts through ErbB-4 [3].
  • The expression of HER3 mRNA correlated strongly to overall survival (P=0.0042); increased expression of HER4 (P=0.0261) and HRG4 (P=0.0245) was also associated with better prognosis [4].

Analytical, diagnostic and therapeutic context of NRG4


  1. Neuregulins 1-4 are expressed in the cytoplasm or nuclei of ductal carcinoma (in situ) of the human breast. Marshall, C., Blackburn, E., Clark, M., Humphreys, S., Gullick, W.J. Breast Cancer Res. Treat. (2006) [Pubmed]
  2. Identification and characterization of novel spliced variants of neuregulin 4 in prostate cancer. Hayes, N.V., Blackburn, E., Smart, L.V., Boyle, M.M., Russell, G.A., Frost, T.M., Morgan, B.J., Baines, A.J., Gullick, W.J. Clin. Cancer Res. (2007) [Pubmed]
  3. Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase. Harari, D., Tzahar, E., Romano, J., Shelly, M., Pierce, J.H., Andrews, G.C., Yarden, Y. Oncogene (1999) [Pubmed]
  4. Expression of HER3, HER4 and their ligand heregulin-4 is associated with better survival in bladder cancer patients. Memon, A.A., Sorensen, B.S., Melgard, P., Fokdal, L., Thykjaer, T., Nexo, E. Br. J. Cancer (2004) [Pubmed]
  5. The epidermal growth factor family has a dual role in deciding the fate of cancer cells. Memon, A.A., Sorensen, S.B., Nexo, E. Scand. J. Clin. Lab. Invest. (2006) [Pubmed]
  6. Co-expression of neuregulins 1, 2, 3 and 4 in human breast cancer. Dunn, M., Sinha, P., Campbell, R., Blackburn, E., Levinson, N., Rampaul, R., Bates, T., Humphreys, S., Gullick, W.J. J. Pathol. (2004) [Pubmed]
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