Induction of a variety of tumors by c-erbB2 and clonal nature of lymphomas even with the mutated gene (Val659----Glu659)

Abstract

The c-erbB2 gene is expressed uniquely in fetal epithelium in vivo and has been suggested to contribute to the development and/or progression of adenocarcinomas in man. In order to assess the oncogenicity of the c-erbB2 gene in vivo, normal c-erbB2 and mutant c-erbB2 encoding glutamic acid instead of valine at position 659 within the transmembrane domain were introduced into mice under the transcriptional regulatory unit of mouse mammary tumor virus long terminal repeat (MMTV-LTR) or immunoglobulin enhancer--SV40 early gene promoter (Ig/Tp). In transgenic mice with normal c-erbB2 under MMTV-LTR, not only adenocarcinomas but also a variety of tumors including B lymphomas were induced at relatively late onset. Induction of pre-B cell lymphomas with normal c-erbB2 was also observed using the Ig/Tp regulatory unit within 6-10 months in some members of one transgenic family among seven lines established. In contrast, with the mutant c-erbB2 under the Ig/Tp regulatory unit, the lymphoma was induced neonatally in all members of four transgenic families among ten lines obtained. However, the immunoglobulin heavy chain gene rearrangement pattern indicated that even with the mutant c-erbB2 the induced lymphomas were clonal.