Autocrine activation of ErbB2/ErbB3 receptor complex by NRG-1 in non-small cell lung cancer cell lines

Lung Cancer. 2004 Feb;43(2):135-43. doi: 10.1016/j.lungcan.2003.08.027.


Our prior studies identified co-expression of the human epidermal growth factor-like receptors 2 (ErbB2) and 3 (ErbB3), as well as the growth factor neuregulin-1 (NRG-1) in normal lung epithelium and lung cancers. As ErbB2 and ErbB3 dimerize to produce a high affinity receptor for NRG-1, we postulated that an autocrine growth loop was present in transformed and non-transformed pulmonary epithelial cells. To test this hypothesis, we examined four cell lines derived from human non-small cell carcinomas for: (1) ErbB2 and ErbB3 expression and endogenous activation; (2) NRG-1 expression and secretion/shedding; and (3) the effect of receptor blockade on autocrine receptor activation. Our studies found that ErbB2 and ErbB3 were expressed by each of these cell lines. In addition, the NRG-1 gene was also expressed with both major isoforms of NRG-1 (NRG-1alpha and NRG-1beta) found intracellularly. Only the NRG-1alpha isoform, however, was found secreted/shed into the culture medium. The secreted/shed NRG-1alpha was capable of activating the ErbB2/ErbB3 receptor complex expressed on the breast adenocarcinoma cell line MCF-7. Basal ErbB2 phosphorylation was identified in all lung cancer cell lines and was inhibited with an antibody that blocked the NRG-1 binding site on ErbB3. Taken together, these data show that secreted NRG-1alpha can activate the ErbB2/ErbB3 heterodimer in an autocrine fashion. The identification of a NRG-1alpha/ErbB2/ErbB3 autocrine loop raises the possibility that interruption of this loop may have therapeutic potential in lung cancer.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Autocrine Communication*
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology*
  • Neuregulin-1 / pharmacology*
  • Receptor, ErbB-2 / biosynthesis*
  • Receptor, ErbB-2 / genetics*
  • Receptor, ErbB-3 / biosynthesis*
  • Receptor, ErbB-3 / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured


  • Neuregulin-1
  • Receptor, ErbB-2
  • Receptor, ErbB-3