Activation and inhibition of the AP-1 complex in human breast cancer cells

Mol Carcinog. 1996 Mar;15(3):215-26. doi: 10.1002/(SICI)1098-2744(199603)15:3<215::AID-MC7>3.0.CO;2-G.


We have studied the expression and activity of the jun and fos families of transcription factors in a panel of human breast cancer cells. Numerous breast-cancer cell lines showed variable levels of expression of jun and fos family-member RNA, activator protein-1 (AP-1) DNA binding, and transcriptional-activating activities during exponential growth. In all of the breast-cancer lines tested, c-jun RNA and AP-1 DNA-binding activity correlated. In addition, in most breast cancer cell lines AP-1 DNA-binding activity also correlates with AP-1-transactivating activity. However, some breast cancer cell lines have high c-jun RNA expression, high AP-1 DNA-binding activity, and low AP-1-transactivating activity. Such results suggest that in these breast cancer cell lines there exist AP-1 complexes that can bind DNA but cannot activate transcription. Multiple peptide growth factors as well as the tumor promoter 12-0-tetradecanoylphorbol-13-acetate induced the expression of jun and fos family-member RNAs and also increased AP-1 DNA-binding activity and functional AP-1-transcriptional activating activity in MCF7 breast cancer cells. However, treatment with estrogen, a steroid growth factor, failed to increase jun and fos RNA expression and induced minimal increases in AP-1 DNA binding and AP-1-induced transcriptional-activating activity in comparison with that seen after peptide hormone treatment. Thus, mitogenic peptide hormones and the tumor promoter 12-0-tetradecanoylphorbol-13-acetate, but not estrogen, strongly activate the AP-1 transcription factor in breast cancer cells. A dominant-negative mutant of c-jun that specifically inhibits AP-1- transactivating activity in rat fibroblasts inhibited AP-1 transactivating activity in breast-cancer cells and blocked the increase in AP-1-mediated transcription induced by serum or specific growth factors. This dominant-negative mutant also inhibited MCF7 colony formation, indicating that expression of this AP-1 inhibitor suppressed the proliferation of these breast cancer cells. Such results suggest that growth factor-induced proliferation of breast cancer cells can possibly be blocked by inhibiting AP-1-transactivating activity.

MeSH terms

  • Base Sequence
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • DNA, Neoplasm / metabolism
  • Gene Expression
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, fos
  • Genes, jun
  • Growth Substances / pharmacology
  • Humans
  • Molecular Sequence Data
  • Neoplastic Stem Cells / drug effects
  • Proto-Oncogene Proteins c-fos / biosynthesis
  • Proto-Oncogene Proteins c-jun / biosynthesis
  • RNA / metabolism
  • Stimulation, Chemical
  • Transcription Factor AP-1 / antagonists & inhibitors*
  • Transcription Factor AP-1 / metabolism
  • Transcription Factor AP-1 / physiology*
  • Tumor Cells, Cultured


  • DNA, Neoplasm
  • Growth Substances
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Transcription Factor AP-1
  • RNA