Effects of MT1 melatonin receptor overexpression on the aromatase-suppressive effect of melatonin in MCF-7 human breast cancer cells

Abstract

A major mechanism through which melatonin reduces the development of breast cancer is based on its antiestrogenic actions by interfering at different levels with the estrogen-signalling pathways. Melatonin inhibits both aromatase activity and expression in vitro (MCF-7 cells) as well as in vivo, thus behaving as a selective estrogen enzyme modulator. The objective of this study was to study the effect of MT 1 melatonin receptor overexpression in MCF-7 breast cancer cells on the aromatase-suppressive effects of melatonin. Transfection of the MT 1 melatonin receptor in MCF-7 cells significantly decreased aromatase activity of the cells and MT 1 -transfected cells showed a level of aromatase activity that was 50% of vector-transfected MCF-7 cells. The proliferation of estrogen-sensitive MCF-7 cells in an estradiolfree media but in the presence of testosterone (an indirect measure of aromatase activity) was strongly inhibited by melatonin in those cells overexpressing the MT 1 receptor. This inhibitory effect of melatonin on cell growth was higher on MT 1 transfected cells than in vector transfected ones. In MT 1 -transfected cells, aromatase activity (measured by the tritiated water release assay) was inhibited by melatonin (20% at 1 nM; 40% at 10 μM concentrations). The same concentrations of melatonin did not significantly influence the aromatase activity of vector-transfected cells. MT 1 melatonin receptor transfection also induced a significant 55% inhibition of aromatase steady-state mRNA expression in comparison to vector-transfected MCF-7 cells (p<0.001). In addition, in MT 1 -transfected cells melatonin treatment inhibited aromatase mRNA expression and 1 nM melatonin induced a higher and significant down-regulation of aromatase mRNA expression (p<0.05) than in vectortransfected cells. The findings presented herein point to the importance of MT 1 melatonin receptor in mediating the oncostatic action of melatonin in MCF-7 human breast cancer cells and confirm MT 1 melatonin receptor as a major mediator in the melatonin signalling pathway in breast cancer.

Basic Mechanisms Involved in the Anti-Cancer Effects of Melatonin

“…The anti-aromatase effects of melatonin on MCF-7 cells require the presence of the MT1 melatonin receptor [129], and have been also described in glioma cells [130]. Furthermore, melatonin potentiates the effects of other antiaromatases such as aminoglutethimide [83].…”

An insight into the scientific background and future perspectives for the potential uses of melatonin

“…It shows apoptosis of Ehrlich ascites carcinoma (EAC) cells and phase delay of the cell cycle [53]. Gonzalez et al demonstrated that melatonin shows oncostatic effect in MCF-7 human breast cancer cells by melatonin receptor 1 (MTR1) thus confirms MTR1 as a main mediator in the melatonin signalling pathway in breast cancer [61]. Further, melatonin inhibits aromatase activity and expression by regulating the gene expression of specific aromatase promoter regions [62].…”

Melatonin inhibits aromatase promoter expression by regulating cyclooxygenases expression and activity in breast cancer cells

“…This modulator effect of melatonin on the enzyme that controls the conversion from androgenic precursors to oestrogens has also been described in vivo in rats bearing DMBA-induced mammary tumours (Cos et al, 2006a). The binding of melatonin to MT 1 receptors has been described as the first step in the antiaromatase action of melatonin on MCF-7 cells (González et al, 2007).…”