DDT stimulates c-erbB2, c-met, and STATS tyrosine phosphorylation, Grb2-Sos association, MAPK phosphorylation, and proliferation of human breast epithelial cells.

Abstract

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.