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Effects of MT<inf>1</inf> 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 anti-estrogenic 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 MT1 melatonin receptor overexpression in MCF-7 breast cancer cells on the aromatase-suppressive effects of melatonin. Transfection of the MT1 melatonin receptor in MCF-7 cells significantly decreased aromatase activity of the cells and MT1- 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 MT1 transfected cells than in vector transfected ones. In MT1-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. MT1 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 MT1- 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 vector-transfected cells. The findings presented herein point to the importance of MT1 melatonin receptor in mediating the oncostatic action of melatonin in MCF-7 human breast cancer cells and confirm MT1 melatonin receptor as a major mediator in the melatonin signalling pathway in breast cancer.