MELATONIN MODULATES GROWTH-FACTOR ACTIVITY IN MCF-7 HUMAN BREAST-CANCER CELLS

Melatonin has been shown to have direct oncostatic actions on estrogen-responsive, MCF-II human breast cancer cells in culture. In the present study, we examined whether these inhibitory actions on cell growth may be mediated through actions on bioassayable growth factor activity. In order to test this hypothesis, we estimated the growth factor activity of conditioned medium (CM) from estradiol (E(2)), or melatonin-treated cells, in the presence or absence of melatonin on MCF-7 cell growth. We also determined whether melatonin inhibits the action of epidermal growth factor (EGF) action in the absence of E(2). The addition of melatonin (10(-9) M) to the cultures of MCF-7 cells with CM from E(2) (10(-8) M)-treated cells significantly inhibited the growth stimulatory activity of CM, suggesting that melatonin inhibited cell proliferation by blocking the action of E(2)-induced autocrine growth stimulatory factors. Conditioned medium from melatonin-treated cells significantly inhibited cell proliferation, while an additional supply of melatonin to these cultures had an even greater inhibitory effect. Melatonin was also active in the complete absence of serum as long as cell growth was stimulated by EGF, an E(2)-inducible growth factor. The inhibitory effect of melatonin increased as the dose of EGF increased. This non-antiestrogenic inhibitory effect of melatonin was reversed by E(2), but not by EGF itself, suggesting that melatonin requires accessible estrogen receptor sites for its inhibitory activity on the growth stimulating action of EGF. Taken together, these findings suggest that melatonin may inhibit the action and/or release of growth stimulatory factors as well as stimulate the release of growth inhibitory factors in culture. Furthermore, these findings indicate an important interaction of melatonin with E(2)-inducible autocrine growth factors such as EGF in the inhibition of MCF-7 cell growth.