The cis decoy against the estrogen response element suppresses breast cancer cells via target disrupting c-fos not mitogen-activated protein kinase activity.
Breast cancer, the most common malignancy in women, has been demonstrated to be associated with the steroid hormone estrogen and its receptor (ER), a ligand-activated transcription factor. Therefore, we developed a phosphorothiolate cis-element decoy against the estrogen response element (ERE decoy) to target disruption of ER DNA binding and transcriptional activity. Here, we showed that the ERE decoy potently ablated the 17beta-estrogen-inducible cell proliferation and induced apoptosis of human breast carcinoma cells by functionally affecting expression of c-fos gene and AP-1 luciferase gene reporter activity. Specificity of the decoy was demonstrated by its ability to directly block ER binding to a cis-element probe and transactivation. Moreover, the decoy failed to inhibit ER-mediated mitogen-activated protein kinase signaling pathways and cell growth of ER-negative breast cancer cells. Taken together, these data suggest that estrogen-mediated cell growth of breast cancer cells can be preferentially restricted via targeted disruption of ER at the level of DNA binding by a novel and specific decoy strategy applied to steroid nuclear receptors.
Intramural Research Support Program, Science Applications International Corporation-Frederick, National Cancer Institute-Frederick, Maryland 21702, USA. lhwang@ncifcrf.gov
Li Hua
LH
Wang
Xiao Yi
XY
Yang
Xiaohu
X
Zhang
Kelly
K
Mihalic
Weihua
W
Xiao
William L
WL
Farrar
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D004958:Estradiol / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D016762:Genes, fos / Q000235:genetics*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009841:Oligonucleotides / Q000235:genetics / Q000494:pharmacology*; D010710:Phosphates / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D009841:Oligonucleotides; D010710:Phosphates; D011960:Receptors, Estrogen; D004958:Estradiol; C083120:phosphorodithioic acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases