ESTROGEN-RECEPTOR TRANSACTIVATION IN MCF-7 BREAST-CANCER CELLS BY MELATONIN AND GROWTH-FACTORS

The pineal hormone, melatonin, inhibits proliferation cf estrogen rece ptor (ER)-positive MCF-7 human breast cancer cells, modulates both ER mRNA and protein expression, and appears to be serum dependent, indica ting interaction between melatonin and serum components. To examine th e effects of melatonin on ER activity, ER transactivation assays were performed by transiently transfecting MCF-7 cells with an ERE-lucifera se reporter construct. MCF-7 cells pre-treated with melatonin for as l ittle as 5 min followed by either epidermal growth factor (EGF) or ins ulin resulted in the estrogen-independent transactivation of the ER. N one of the compounds when used alone transactivated the ER. The abilit y of melatonin and EGF to transactivate the ER was abolished by the ad dition of the antiestrogen, ICI 164384, suggesting that melatonin and EGF co-operate to transactivate the ER. The modulation of ER transacti vation was associated with changes in mitogen activated protein kinase activity and ER phosphorylation. This ER transactivation was blocked by pertussis toxin, a G(alpha i)-protein-coupled receptor inhibitor, s uggesting cross talk between the G-protein-coupled melatonin receptor pathway and the EGF/insulin tyrosine kinase receptor pathways in modul ating ER transactivation. Exactly how the ability of melatonin in comb ination with EGF to transactivate the ER relates to melatonin's observ ed growth suppressive effects is not clear. It is possible that, altho ugh melatonin and EGF transactivate the ER, this transactivation does not result in the full transcription of estrogen-responsive genes, but rather, makes the ER refractory to activation by estradiol, thus, blo cking the mitogenic actions of estradiol. (C) 1998 Elsevier Science Ir eland Ltd. All rights reserved.