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

Hang Zhou, Lili Liu, Keunmyoung Lee, Xiusheng Qin, Adam W. Grasso, Hsing Jien Kung, Joesph E. Willis, Jeffery Kern, Thomas Wagner, Stanton L. Gerson

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Abstract

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.

Original languageEnglish
Pages (from-to)8732-8740
Number of pages9
JournalOncogene
Volume21
Issue number57
DOIs
Publication statusPublished - Dec 12 2002
Externally publishedYes

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Keywords

  • Erb-B-2
  • Erb-B-3
  • K-ras
  • Lung tumor
  • Methylnitrosourea
  • Transgenic mice

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Zhou, H., Liu, L., Lee, K., Qin, X., Grasso, A. W., Kung, H. J., Willis, J. E., Kern, J., Wagner, T., & Gerson, S. L. (2002). Lung tumorigenesis associated with erb-B-2 and erb-B-3 overexpression in human erb-B-3 transgenic mice is enhanced by methylnitrosourea. Oncogene, 21(57), 8732-8740. https://doi.org/10.1038/sj.onc.1205984