DDT stimulates c-erbB2, c-met, and STATS tyrosine phosphorylation, Grb2-Sos association, MAPK phosphorylation, and proliferation of human breast epithelial cells.
Several environmental organochlorines, some of which exhibit estrogenic activity, have been detected in human breast tissue and have been suggested as having a role in tumorigenesis. In this communication, we report the effects of DDT on c-erbB2 and c-met growth factor receptor tyrosine kinase and STATS signal transduction processes in human breast epithelial MCF-10A cells. p,p'-DDT at physiologically relevant concentrations (i.e. 10 nM) elevated c-erbB2, c-met and STAT1 alpha (p84/91) tyrosine phosphorylation, stimulated Grb2-Sos1 association and elevated MAPK phosphorylation. In contrast, o,p'-DDT under identical conditions failed to stimulate either c-erbB2 or c-met tyrosine phosphorylation, demonstrating a structural specificity for this effect. p,p'-DDT also stimulated breast epithelial cell proliferation, as evidenced by 3H thymidine incorporation and analysis of cell doubling times. These results provide evidence of additional pathways by which environmental chemicals may stimulate cell proliferation and/or tumorigenesis and thereby function as xenomitogens.
Shen
K
K
Institute of Chemical Toxicology, Wayne State University, Detroit, Michigan 48201, USA.
Novak
R F
RF
D048868:Adaptor Proteins, Signal Transducing; D001940:Breast / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003634:DDT / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D051380:GRB2 Adaptor Protein; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D003634:DDT; D004268:DNA-Binding Proteins; D051380:GRB2 Adaptor Protein; D020662:Guanine Nucleotide Exchange Factors; D019000:Phosphotyrosine; D011506:Proteins; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; C495948:GRB2 protein, human; C494079:STAT1 protein, human