Melatonin exerts oncostatic effects on different kinds of neoplasias, especially on estrogen-dependent mammary tumors. Current knowledge about the mechanisms by which melatonin inhibits the growth of breast cancer cells point to an interaction of melatonin with estrogen-responsive pathways. The intratumoral production of estrogens in breast carcinoma tissue plays a pivotal role in the proliferation of mammary tumoral cells and its blockade is one of the main objectives of the treatment of breast cancer. The aim of the present work is centered on the study of the role of melatonin in the control of some enzymes involved in the formation and transformation of estrogens in human breast cancer cells. The present study demonstrates that melatonin, at physiologic concentrations, modulates the synthesis and transformation of biologically active estrogens in MCF-7 cells, through the inhibition of sulfatase (STS) and 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) activity and expression, enzymes involved in the estradiol formation in breast cancer cells. Physiologic concentrations of melatonin also stimulate the activity and expression of estrogen sulfotransferase (EST), the enzyme responsible for the formation of the biologically inactive estrogen sulfates. The level of EST mRNA steady-state of cells treated with melatonin was three times higher than that in control cells. These findings which document that melatonin has an inhibitory effect on STS and 17beta-HSD1 and a stimulatory effect on EST, in combination with its previously described antiaromatase effect, can open up new and interesting possibilities in clinical applications of melatonin in breast cancer.

Serotonin, one of the most important neurotransmitters in the central nervous system, is synthesized by the amino acid, tryptophan. Given that this essential amino acid is consumed in the diet, the aim of this study was to evaluate the effect of orally administered L-tryptophan (125 mg/kg) on circadian variations in the levels of serotonin in brain and plasma. We used male Wistar rats of 14 ± 2 weeks of age (n = 240), maintained under conditions of a 12-hr light:dark cycle, and food and water ad libitum . Tryptophan administration was by gavage in a daily single dose at 7 p.m. for 7 days. The serotonin levels were measured by ELISA every hour at night (8 p.m. to 8 a.m.) and every 4 hr during daytime (8 a.m. to 8 p.m.). The results show that in both the tryptophan-treated and untreated groups the highest values appeared during the beginning of the darkness with a peak at 9, 10 and 11 p.m. in controls, and at 9 p.m. in the tryptophan-treated group. After tryptophan administration, the levels of serotonin were significantly higher in the plasma and all the brain regions analysed than in the control group. This increase of serotonin levels was greater in the pineal gland than in other brain regions, and the least in plasma. In conclusion, oral administration of tryptophan during 7 days enhances serotonin levels over a 24-hr period, and produces an advance in the peak of serotonin in both plasma and different brain regions.Circadian rhythms are generated and maintained by the biological clock located in the suprachiasmatic nucleus [1,2]. Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter strongly implicated in the regulation of these rhythms [3]. It is also involved in many functions throughout the brain, playing an important role in behaviour, depression, mood regulation, cognitive function, anxiety, sleep, appetite, sexual function, blood flow to the brain [4], and also has a fundamental role of precursor in melatonin synthesis.The synthesis and release of 5-HT are subject to circadian variations. Barassin et al . [5] and Dudley et al . [6] described in suprachiasmatic nucleus of rats and hamsters, respectively, that the maximum levels in release of 5-HT were obtained at the light/dark transition, just at the beginning of the dark phase, after which output of 5-HT decreased to basal levels throughout the remainder of the night. In previous research [7], we noted in rats that the peaks of 5-HT in basal conditions in plasma and different brain regions (pineal gland, hypothalamus, hippocampus, cerebellum and striatum) appear at the beginning of the dark period. This pattern can be altered in vitro by the use of 5-HT agonists acting at the level of the 5-HT1A receptors, with advance of the diurnal phase and delay of the nocturnal phase [8]. It has been found not only that this pattern of production of 5-HT persists in conditions of constant darkness [9][10][11], but also that it is influenced by luminosity signals [11,12]. Both the synthesis and the diurnal release of this neurotransmitte...

Cadmium (Cd) is a heavy metal classified as a human carcinogen. Occupational exposure, dietary consumption and cigarette smoking are sources of Cd contamination. Cd-induced carcinogenicity depends on its oxidative and estrogenic actions. A possible role of Cd in breast cancer etiology has been recently suggested. Melatonin, because of its antioxidant and antiestrogenic properties could counteract the toxic effects of this metalloestrogen. Our aim was both to determine the effects of relevant doses of Cd on mice mammary glands and uterus and to test whether melatonin would counteract its effects. Female mice of different ages and estrogenic status (prepuberal, adult intact, adult ovariectomized) were treated with CdCl(2) (2-3 mg/kg, i.p.), melatonin (10 microg/mL in drinking water), CdCl(2) + melatonin, or diluents. Whereas in prepuberal animals Cd disturbs mammary ductal growth and reduces the number of terminal end buds, in adults, regardless of the steroidal milieu, Cd exerts estrogenic effects on mammary glands, increasing lobuloalveolar development and ductal branching. Uterine weight also increased as a result of Cd treatment. The effects of Cd are partially inhibited by melatonin. In adult ovariectomized mice, Cd concentration in blood of animals treated with CdCl(2) + melatonin was lower than in mice receiving only Cd; the opposite effects were found in non-castrated animals. As Cd mimics the effect of estrogens, the high incidence of breast cancer in tobacco smokers and women working in industries related with Cd could be explained because of the properties of this metal. The effects of melatonin point to a possible role of this indoleamine as a preventive agent for environmental or occupational Cd contamination.

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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.