Activation and inhibition of the AP-1 complex in human breast cancer cells.
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.
Chen
T K
TK
Biomarkers and Prevention Research Branch, Division of Cancer Prevention and Control, National Cancer Institute, Rockville, Maryland, USA.
Smith
L M
LM
Gebhardt
D K
DK
Birrer
M J
MJ
Brown
P H
PH
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016762:Genes, fos; D016758:Genes, jun; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D012313:RNA / Q000378:metabolism; D013268:Stimulation, Chemical; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D006133:Growth Substances; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D012313:RNA