Melatonin inhibits estrogen receptor transactivation and cAMP levels in breast cancer cells

We have previously demonstrated that the pineal hormone, melatonin, can inhibit the growth of estrogen receptor-alpha (ER alpha)-positive breast cancer cells and suppress ER alpha gene transcription. To investigate the relationship between the estrogen response pathway and melatonin's growth inhibition, ER alpha -positive MCF-7 human breast cancer cells were transiently transfected with an estrogen response element (ERE) luciferase reporter construct and then treated with melatonin (10(-)9-10(-)6 M) for 30 min followed by 10(-)9 M 17-beta -estradiol (E2) or treated with each compound alone. Melatonin pre-treatment significantly reduced E2-induced ER alpha transactivation and ER alpha -ERE binding activity. We also conducted experiments to determine if melatonin modulates cAMP levels in MCF-7 cells. Melatonin inhibited the forskolin-induced and E2-induced elevation of cAMP levels by 57 and 45%, respectively. These data indicate that melatonin can act as a biological modifier to affect ER alpha transcriptional activity by regulating signal transduction pathways which impinge on the ER alpha and by altering E2-mediated ER alpha transactivation and ER alpha DNA binding activity.