The oncostatic effects of melatonin on the mammary gland have been studied in transgenic mice carrying the N-ras proto-oncogene under the control of the MMTV-LTR. Female (4-week-old) virgin mice with positive transgenic pedigrees were injected with melatonin (200 micrograms/mouse/ day, five times a week) or vehicle late in the evening. After 5 months of treatment, animals were sacrificed and the mammary glands were dissected for whole mounts, histology, and immunohistochemical analysis with a mouse monoclonal antibody specific for N-ras protein. Mammary glands of control transgenic mice showed different densities of hyperplastic alveolar nodules (HANs) consisting primarily of dysplastic epithelial cells with nuclear atypia and prominent nucleoli. The epithelial cells of HANs showed a high expression of N-ras while no immunostaining was detected in the unaffected mammary parenchyma. Only one (10%) of the control transgenic mice presented an infiltrating ductal carcinoma with the neoplastic cells overexpressing N-ras protein. The mammary glands of melatonin treated mice had a lower density of HANs, absence of epithelial dysplastic cells, and weak immunostaining of N-ras protein in comparison to the vehicle-treated group. None of the melatonin treated animals developed mammary carcinomas during the observation period. The lymph nodes of the inguinal mammary glands of all the vehicle-treated transgenic mice presented hyperplasia and two animals even had lymphomas, whereas in melatonin-treated animals there was less hyperplasia (two cases were atrophic) and a lack of lymphomas. We conclude that in the mammary glands of MMTV-LTR/N-ras transgenic female virgin mice, melatonin a) reduces the incidence of HANs and the expression of N-ras protein in focal hyperplastic lesions, b) completely prevents the development of epithelial cell atypia and mammary adenocarcinomas, and c) also reduces the hyperplasia of the mammary lymphoid tissue and prevents the development of lymphomas.

The effect of prolonged, oral melatonin treatment on spontaneous mammary tumor development in female C3H/Jax mice was studied. Melatonin was administered at a dose of 25 micrograms/mouse/day from 21 to 44 days of age and 50 micrograms/mouse/day from day 45 onwards. By the age of 12 months, 62.5% of control animals developed tumors as opposed to 23.1% in the melatonin treated group (P less than 0.02). In both control and treated mice, the thoracic pairs of mammary glands were obviously more susceptible to spontaneous mammary tumor development, as at least 50% of the total tumors developed in this region. Reduction in submaxillary and pituitary gland weights of treated animals was observed at necropsy (P less than 0.001). Decreased serum 17-beta-estradiol (E2) levels in melatonin treated mice (P less than 0.05) and a marked reduction in [3H]thymidine incorporation into DNA of melatonin-treated mammary glands (P less than 0.02) positively correlated with the sparse mammary gland development seen in these mice. These observations indicate that at the given dose level, melatonin modulates the degree of development of the mammary epithelium, subsequently reducing spontaneous mammary tumor incidence in these high risk mice.

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Daily treatment of ‘functionally’ and surgically pinealectomized female Holtzman rats reared in continuous light (light: dark schedule, 24L:OD) with oral melatonin (100 pig/day/rat) initiated 30 days prior to and 90 days following 9,10-dimethyl-1,2-benzanthracene (DMBA) administration on day 55 of age, resulted in a highly significant suppression of mammary tumor incidence and prolongation of latency period of tumor appearance (p <0.001). An identical treatment schedule of melatonin to intact rats given DMBA, housed in short photoperiods (10L:14D), also resulted in a significant suppression of tumor incidence (p <0.05), though the latency period of tumor appearance was not prolonged. These results demonstrate for the first time that replacement or additive manipulations of melatonin from puberty to adulthood plays a critical role in the suppression of DMBA-induced mammary tumors.

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