Amplification of Ki-ras and elevation of MAP kinase activity during mammary tumor progression in C3(1)/SV40 Tag transgenic mice

Oncogene. 1998 Nov 5;17(18):2403-11. doi: 10.1038/sj.onc.1202456.


We have previously documented that transgenic mice expressing SV40 Tag regulated by the rat prostatic steroid-binding protein C3(1) 5'-flanking region display multistage mammary tumorigenesis. To delineate genetic changes associated with mammary tumor progression, comparative genomic hybridization (CGH) was performed. CGH revealed a consistent gain of the telomeric region of chromosome 6. This region contains the Ki-ras proto-oncogene. Analyses of genomic DNA by Southern blot demonstrated up to 40-fold amplification of the Ki-ras gene. Ki-ras amplification was detected in 12, 46 and 68% of tumors from 4, 5 and 6 month old mice, respectively, whereas no amplifications were found in any preneoplastic mammary tissues. Tumors bearing Ki-ras gene amplification exhibited high levels of Ki-ras RNA and protein. The over-expressed Ki-Ras protein in these tumors appeared functionally active as indicated by the elevated MAP kinase activity. These data demonstrate that while Ki-ras amplification might not be an early event, there is a strong association between Ki-ras amplification and over-expression and mammary tumor progression in this model. This study also shows that CGH is a powerful and useful technique for identifying chromosomal copy number changes during tumor progression, and that this model may provide a predictable in vivo system for studying gene amplification.

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Disease Progression
  • Gene Amplification*
  • Genes, ras / genetics*
  • Guanosine Diphosphate / metabolism
  • Guanosine Triphosphate / metabolism
  • In Situ Hybridization, Fluorescence
  • Mammary Neoplasms, Animal / genetics*
  • Mice
  • Mice, Transgenic
  • Mutation
  • RNA, Messenger / metabolism
  • Receptor, ErbB-2 / metabolism
  • ras Proteins / metabolism


  • RNA, Messenger
  • Guanosine Diphosphate
  • Guanosine Triphosphate
  • Receptor, ErbB-2
  • Calcium-Calmodulin-Dependent Protein Kinases
  • ras Proteins