Synthetic estrogens-mediated activation of JNK intracellular signaling molecule

Signal transduction pathways regulate the transmission of specific signals to the cells from the surface to the nucleus. Activation of protein kinases such as JNKs (c-jun amino-terminal kinase), a subgroup of the mitogen acti vated protein kinase (MAPK) family, results in regulation of important cell ular functions like cell growth and differentiation. The involvement of est rogens in stimulation of growth of already transformed breast cancer cells in vivo and in vitro accompanied with activation of JNKs prompted us to inv estigate the role of synthetic estrogens in the regulation of JNK expressio n. T 47D breast cancer cells were incubated with the synthetic estrogens, ethi nylestradiol (10(-9)M) and 17 beta -estradiol valerate (10(-9)M), epidermal growth factor (EGF) (10 ng/ml) and the natural estrogen, 17 beta -estradio l (10(-9)M), for 5 minutes. The same experiments were repeated after pretre atment of the cells with ICI 182780 for 24 hours. EGF as well as natural an d synthetic estrogens stimulated proliferation. This effect was reversed by the estrogen receptor blocker ICI 182780, but only in the case of both nat ural and synthetic estrogen. Like 17 beta -estradiol, synthetic estrogens i nduced a rapid and transient activation of JNK kinase. ICI 182780 blocked t his effect, but not that mediated by EGF. Ethinylestradiol used in oval contraceptives, and 17 beta -estradiol and 17 beta -estradiol valerate for hormone replacement therapy, are able to acti vate JNK. The estrogen receptor is necessary for JNK activation upon estrog en stimulation.