Lung tumorigenesis associated with erb-B-2 and erb-B-3 overexpression in human erb-B-3 transgenic mice is enhanced by methylnitrosourea

Oncogene. 2002 Dec 12;21(57):8732-40. doi: 10.1038/sj.onc.1205984.


Erb-B-3 overexpression is associated with poor prognosis in non-small cell lung cancer and is often overexpressed in breast cancers. MMTVhuman-erb-B-3 transgenic mice were generated to evaluate the impact of erb-B-3 overexpression on lung and mammary gland tumorigenesis. These transgenic mice developed a high incidence of lung adenocarcinomas but not mammary gland tumors. The tumors overexpressed transgenic human [h]-erb-B-3 but also overexpressed endogenous erb-B-2, indicating that the heterodimer of h-erb-B-3-erb-B-2 was required for proliferative signal transduction to the nucleus. Lung tumor latency was shorter and the incidence higher in erb-B-3 transgenic mice treated with the methylating agent, methylnitrosourea [MNU]. In MNU treated mice, K-ras activating point mutations in codon 12, synergized with h-erb-B-3 in lung tumorogenesis. In bitransgenic MMTVrat-erb-B2/MMTV-human-erb-B-3 mice, lung tumor latency was also significantly shortened. Unlike over-expression of rat-erb-B-2, overexpression of h-erb-B-3 did not alter the incidence or latency of mammary tumors. Coupled erb-B-2 and erb-B-3 overexpression as well as K-ras activation induced signaling through mitogen-activated protein kinase (MAPK). This animal model links erb-B-3 with lung cancer, suggests that erb-B-2 and erb-B-3 heterodimerization is a necessary intermediate, and documents latency shortening by methylating agent-induced mutation of K-ras. This erb-B-3 mouse lung cancer model will help dissect genetic changes in lung tumorigenesis and may be useful for chemoprevention studies.

Publication types

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

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung / chemically induced
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Genes, erbB*
  • Genes, erbB-2*
  • Genes, ras
  • Humans
  • Lung Neoplasms / chemically induced
  • Lung Neoplasms / genetics*
  • Methylnitrosourea / toxicity*
  • Mice
  • Mice, Transgenic
  • Mutation
  • Transgenes


  • Methylnitrosourea