The effect of melatonin treatment regimen on mammary adenocarcinoma development in HER‐2/neu transgenic mice

Abstract

The effect of various regimens of treatment with melatonin on the development of mammary tumors in HER2/neu transgenic mice was investigated. Female HER-2/neu mice starting from the age of 2 months were kept under standard light/dark regimen and as given melatonin with tap water (20 mg/l) during the night time 5 times monthly (interrupted treatments) or constantly to natural death. Intact mice served as controls. Treatment with melatonin slowed down age-related disturbances in estrous function most in the group exposed to interrupted treatment with the hormone. Constant treatment with melatonin decreased incidence and size of mammary adenocarcinomas, and incidence of lung metastases, compared to controls. The number of mice bearing 4 and more tumors was reduced in the group with constant melatonin treatment. Interrupted treatment with melatonin promote mammary carcinogenesis in HER-2/neu transgenic mice. The data demonstrate the regimen-dependent inhibitory effect of melatonin on the development of spontaneous mammary tumors in HER-2/neu mice but not on overall survival with implication about the likely cause of the effect. Polycystic kidney disease is common in this transgenic line. Adverse effect of melatonin on the life span in our study may be unique to the transgenic model used and may not be relevant to the suppressive effect of melatonin in delay of mammary cancer. © 2002 Wiley-Liss, Inc. Key words: melatonin; HER-2/neu, transgenic mice; mammary cancerBreast cancer is one of the most common cancers and is a leading cause of mortality in women. 1,2 The HER-2/neu oncogene encodes a 185 kDa (p 185) receptor protein that belongs to the epidermal growth factor receptor family involved in organogenesis and epithelial differentiation. 3 Amplification and mutation of HER-2/neu plays a pathogenetic role in several malignancies, including carcinoma of the breast, ovary and uterus. 4,5 Overexpression of ErbB-2/HER-2/neu occurs in 15-40% of human breast cancers. 6 Its appearance is correlated with poor prognosis and is therefore an important target for physiologic investigation and therapeutic intervention. 5 It was shown that treatment with pineal indole hormone melatonin inhibits the development of carcinogeninduced or transplanted tumors in the mammary gland, uterine cervix and colon in various animal models. [7][8][9][10] It is worthy of note that in the majority of in vivo studies only 1 dose and regimen of treatment with melatonin has been investigated; however in vitro studies have shown the dose-dependent effect of the hormone on tumor growth. 9,10 At present, several mechanisms for the effect of melatonin on mammary cancer tumorigenesis have been proposed: an endocrine hypothesis, 9,10 based on the effects of melatonin on pituitary or sex hormones controlling mammary gland development, and a direct action on tumor cells through melatonin-mediated antiproliferative, antioxidant or immunoenhancing effects. 10 Recently by using the HER-2/neu transgenic mice as a model of mammary carcinogenesis, we showed an inh...

Short-term effects of night shift work on breast cancer risk: a cohort study of payroll data

“…ER+/HER2-tumors constituted 88% of the ER+ tumors in this material and the decreased risk we observed for this subtype is not supportive of earlier studies showing associations between night shift work and ER+ tumors (without information on HER2 receptor status) (25)(26)(27)(28). Experimental studies implicate melatonin suppression in HER2+ carcinogenesis (45,46).…”

Metformin extends life span of HER-2/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumors in vivo

“…[43][44][45][46] The anti-diabetics biguanides inhibit fatty acid oxidation, suppress gluconeogenesis in the liver, increase the availability of insulin receptors, inhibit monoamine oxidase, 46 increase sensitivity of Secondly, our results alongside with recent findings of mTOR signaling pathway involvement in regulation of aging 57 and evidence of significant life span extension of mammals with rapamycin and calorie restriction, [50][51][52] suggest that mimetic of calorie restriction, anti-diabetic biguanide metformin may be rapidly contemplated for pharmacological intervention at a population level. 10 ad libitum. Cancer prevention study.…”

“…9 Treatment with melatonin inhibits development of mammary tumors in a number of another models both in vitro and in vivo. [10][11][12] In this paper, we for the first time present the results of study of effect of combined treatment with metformin and melatonin on some aging related biological parameters, on the survival and Population studies have shown that treatment with the antidiabetic biguanide metformin significantly reduced cancer risk. In our animal studies, metformin delayed the onset of mammary adenocarcinoma (MAC) in transgenic HeR-2/neu mice but not the onset of spontaneous mammary tumors in female SHR mice.…”

Effect of exposure to light‐at‐night on life span and spontaneous carcinogenesis in female CBA mice

“…There is evidence of the oncostatic effect of melatonin on mammary tumor growth in vitro and in vivo experiments. [2][3][4][5][6]18,33,42 There are data on the inhibitory effect of melatonin on DMBA-induced cervicovaginal carcinogenesis in mice 43 and 1,2-dimethylhydrazine-induced colon carcinogenesis in rats. 44,45 Mechanisms of the inhibitory effect of melatonin on carcinogenesis include a variety of possibilities, discussed in several comprehensive reviews and include antioxidant and antiproliferative effects, increase in apoptosis and inhibitory effect on telomerase activity in tumor cells in vivo and in vitro, antiestrogenic effects, decreased IGF-1 and insulin levels, etc.…”

“…There are data on synthesis and secretion of melatonin by pineal gland of CBA mice. 17 Mice were randomly subdivided into 2 groups and kept 5 per polypropylene cages (30 ϫ 21 ϫ 10 cm) under standard light/dark regimen (12 hr light:12 hr darkness; LD) or constant light regimen (LL) at a temperature of 22 Ϯ 2°C and received standard laboratory chow 18 and tap water ad lib.…”