Effects of melatonin on mammary gland lesions in transgenic mice overexpressing N‐rasproto‐oncogene

Abstract

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.

Melatonin and mammary cancer: a short review.

“…Thus, transgenic mice overexpressing the N-ras protooncogene under the transcriptional control of the MMTVmouse mammary tumor virus -long terminal repeat (LTR) develop hyperplasic alveolar nodules (premalignant lesions) as well as mammary adenocarcinomas. The treatment of these transgenic mice with melatonin significantly reduces the incidence of these mammary lesions, the expression of N-ras protein in focal hyperplasic lesions, and the incidence of adenocarcinomas (Mediavilla et al 1997). In transgenic mice expressing the c-neu breast cancer oncogene under the control of an MMTV promoter, melatonin delayed the appearance of palpable tumors and the growth of the tumors (Rao et al 2000).…”

Shift work and cancer – considerations on rationale, mechanisms, and epidemiology

“…Melatonin exerts an anti-estrogenic effect via interaction with ERα (94-95) and counteracts the effects of estradiol on breast cancer cell proliferation, invasiveness, and telomerase activity (96-100). Melatonin down-regulates both the expression of protein growth factors and proto-oncogens stimulated by estrogen (101,102) and the epidermal growth factor receptor 2 (HER2/neu), the expression of which is associated with increased malignancy in some forms of human breast cancer (103). Melatonin modulates local estrogen biosynthesis (which is of special importance in post-menopausal breast cancer) by reducing aromatase expression and activity (104,105).…”

Cancer Incidence among Female Flight Attendants: A Meta-Analysis of Published Data

“…5 Melatonin was found to have oncosuppressive properties on melanoma cells 35,36 and an oncostatic effect on mammary glands both in vivo and in vitro. 37,38 Melatonin could also act as a naturally occurring antiestrogen, thereby influencing the proliferative rate of mammary tumor cells. 39,40 Epidemiological evidence confirmed a higher rate of breast cancer with increasing duration of nighttime employment 41,42 and degree of visual impairment in women.…”