Melatonin inhibits the growth of breast cancer cells by interacting with estrogen-responsive pathways, thus behaving as an antiestrogenic hormone. Recently, we described that melatonin reduces aromatase expression and activity in MCF-7 human breast cancer cells, thus modulating the local estrogen biosynthesis. To investigate the in vivo aromatase-inhibitory properties of melatonin in our current study, this indoleamine was administered to rats bearing DMBA-induced mammary tumors, ovariectomized (ovx) and treated with testosterone. In these castrated animals, the growth of the estrogen-sensitive mammary tumors depends on the local aromatization of testosterone to estrogens. Ovariectomy significantly reduced the size of the tumors while the administration of testosterone to ovx animals stimulated tumor growth, an effect that was suppressed by administration of melatonin or the aromatase inhibitor aminoglutethimide. Uterine weight of ovx rats, which depends on the local synthesis of estrogens, was increased by testosterone, except in those animals that were also treated with melatonin or aminoglutethimide. The growth-stimulatory effects of testosterone on the uterus and tumors depend exclusively on locally formed estrogens, since no changes in serum estradiol were appreciated in testosterone-treated rats. Tumors from animals treated with melatonin had lower microsomal aromatase activity than tumors of animals from other groups, and incubation with melatonin decreased the aromatase activity of microsomal fractions of tumors. Animals treated with melatonin had the same survival probability as the castrated animals and significantly higher survival probability than the uncastrated. We conclude that melatonin could exert its antitumoral effects on hormone-dependent mammary tumors by inhibiting the aromatase activity of the tumoral tissue. ' 2005 Wiley-Liss, Inc.Key words: melatonin; pineal; DMBA; breast cancer; aromatase Melatonin, the main hormone secreted by the pineal, is an indoleamine that acts as a regulator of neoplastic cell growth, particularly on endocrine-responsive breast cancer. [1][2][3][4] In this regard, the most common conclusion is that melatonin, in vivo, reduces the incidence and growth of chemically induced mammary tumors in rodents.3 In vitro, melatonin, at concentrations corresponding to the physiologic levels present in human blood during the night, inhibits proliferation, increases expression of p53 and reduces the invasiveness of the estrogen-responsive MCF-7 human breast cancer cells.3-9 Different hypotheses, including the immunomodulatory actions of melatonin, 10 its antioxidative effects 11 or the inhibition of telomerase activity, 12 have been postulated to explain the oncostatic properties of melatonin. However, the effects of melatonin on mammary cancer have been mostly considered as a consequence of its interaction with the estrogen-signaling pathway 13 by 2 different mechanisms: (i) by downregulating gonadal synthesis of steroids and, consequently, decreasing their circulating levels; ...

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.

This paper describes a morphometric study of the evolution of tubulointerstitial nephropathy in adriamycin-induced focal and segmental glomerulosclerosis in Wistar rats over 32 weeks old. The earliest changes were located in the glomeruli. In the 10 week of the study, tubulointerstitial nephropathy appeared and, although the interstitial space increased after the 2nd week, this increase only became statistically significant after the 10 week. Proteinuria showed the highest correlation with the interstitial space, however, the interstitial space showed the highest correlation indices with the total number of glomeruli affected and to a lesser extent with adhesions to and thickening of Bowman’s capsule.

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