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Melatonin and mammary cancer: a short review
E J Sánchez-Barceló1, S Cos, R Fernández
1Department of Physiology and Pharmacology, School of Medicine, University of Cantabria, 39011 Santander, Spain. barcelo@unican.es
Abstract:
Melatonin is an indolic hormone produced mainly by the pineal gland. The former hypothesis of its possible role in mammary cancer development was based on the evidence that melatonin down-regulates some of the pituitary and gonadal hormones that control mammary gland development and which are also responsible for the growth of hormone-dependent mammary tumors. Furthermore, melatonin could act directly on tumoral cells, as a naturally occurring antiestrogen, thereby influencing their proliferative rate. The first reports revealed a low plasmatic melatonin concentration in women with estrogen receptor (ER)-positive breast tumors. However, later studies on the possible role of melatonin on human breast cancer have been scarce and mostly of an epidemiological type. These studies described a low incidence of breast tumors in blind women as well as an inverse relationship between breast cancer incidence and the degree of visual impairment. Since light inhibits melatonin secretion, the relative increase in the melatonin circulating levels in women with a decreased light input could be interpreted as proof of the protective role of melatonin on mammary carcinogenesis. From in vivo studies on animal models of chemically induced mammary tumorigenesis, the general conclusion is that experimental manipulations activating the pineal gland or the administration of melatonin lengthens the latency and reduces the incidence and growth rate of mammary tumors, while pinealectomy usually has the opposite effects. Melatonin also reduces the incidence of spontaneous mammary tumors in different kinds of transgenic mice (c-neu and N-ras) and mice from strains with a high tumoral incidence. In vitro experiments, carried out with the ER-positive MCF-7 human breast cancer cells, demonstrated that melatonin, at a physiological concentration (1 nM) and in the presence of serum or estradiol: (a) inhibits, in a reversible way, cell proliferation, (b) increases the expression of p53 and p21WAF1 proteins and modulates the length of the cell cycle, and (c) reduces the metastasic capacity of these cells and counteracts the stimulatory effect of estradiol on cell invasiveness; this effect is mediated, at least in part, by a melatonin-induced increase in the expression of the cell surface adhesion proteins E-cadherin and beta(1)-integrin. The direct oncostatic effects of melatonin depends on its interaction with the tumor cell estrogen-responsive pathway. In this sense it has been demonstrated that melatonin down-regulates the expression of ERalpha and inhibits the binding of the estradiol-ER complex to the estrogen response element (ERE) in the DNA. The characteristics of melatonin's oncostatic actions, comprising different aspects of tumor biology as well as the physiological doses at which the effect is accomplished, give special value to these findings and encourage clinical studies on the possible therapeutic value of melatonin on breast cancer.
Insights
Melatonin, a hormone from the pineal gland, shows promise in fighting breast cancer. Studies indicate it inhibits tumor growth and spread by interacting with estrogen pathways, suggesting potential therapeutic benefits.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Melatonin, an indolic hormone primarily from the pineal gland, was hypothesized to influence mammary cancer due to its regulation of pituitary and gonadal hormones.
- Melatonin's potential antiestrogenic activity and observed low levels in women with estrogen receptor (ER)-positive breast tumors suggested a role in breast cancer development.
- Epidemiological studies noted lower breast cancer incidence in blind women, correlating with increased melatonin levels due to reduced light exposure.
Purpose of the Study:
- To investigate the role of melatonin in mammary cancer development and progression.
- To evaluate the direct effects of melatonin on estrogen receptor-positive breast cancer cells.
- To explore the potential therapeutic value of melatonin in breast cancer treatment.
Main Methods:
- Review of epidemiological data linking visual impairment, melatonin levels, and breast cancer incidence.
- Analysis of in vivo studies on animal models (chemically induced and transgenic) of mammary tumorigenesis.
- In vitro experiments using ER-positive MCF-7 human breast cancer cells treated with physiological melatonin concentrations.
Main Results:
- Animal studies showed that melatonin administration reduced mammary tumor incidence, latency, and growth rate.
- In vitro studies demonstrated melatonin's inhibition of MCF-7 cell proliferation, modulation of cell cycle proteins (p53, p21WAF1), and reduced metastatic capacity.
- Melatonin counteracted estradiol's stimulatory effects on cell invasiveness by upregulating E-cadherin and beta(1)-integrin, and directly downregulated ERalpha expression and estradiol-ER complex binding to DNA.
Conclusions:
- Melatonin exhibits direct oncostatic effects on breast cancer cells by interacting with the estrogen-responsive pathway.
- Its ability to inhibit proliferation, reduce invasiveness, and modulate key proteins supports its potential as a therapeutic agent.
- Findings encourage further clinical studies on melatonin's efficacy in treating breast cancer.