The role of pineal gland in breast cancer development

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Abstract

The role of the modulation of the pineal gland function in development of breast cancer is discussed in this review. An inhibition of the pineal function with pinealectomy or with the exposure to the constant light regimen stimulates mammary carcinogenesis, whereas the light deprivation inhibits the carcinogenesis. Epidemiological observations on increased risk of breast cancer in night shift workers, flight attendants, radio and telegraph operators and on decreased risk in blind women are in accordance with the results of experiments in rodents. Treatment with pineal indole hormone melatonin inhibits mammary carcinogenesis in pinealectomized rats, in animals kept at the standard light/dark regimen (LD) or at the constant illumination (LL) regimen. Pineal peptide preparation Epithalamin and synthetic tetrapeptide Epitalon (Ala–Glu–Asp–Gly) are potent inhibitors of mammary carcinogenesis in rodents and might be useful in the prevention of breast cancer in women at risk.

Introduction

According to the International Agency for Research on Cancer report [1], breast cancer constituted a huge disease burden in developed countries in the year 2000. It is the most common cancer in women with an estimated 999,000 new cases of breast cancer each year (≈22% of cancers in women) resulting in some 375,000 deaths. More than half of all cases are registered in industrialized countries: about 335,000 in Europe and 195,000 in North America. The disease is not yet as common among women in developing countries although an incidence is increasing. Risk of breast cancer incidence had been associated with higher socio-economic status, such as income, education, housing, etc. as they were related to such health factors as age at menstruation and menopause, obesity, height, alcohol consumption, late age at first birth, low parity, estrogen replacement therapy, some diet habits, etc. Two environmental factors introduced ≈100 years ago—electricity and artificial light—dramatically changed the lifestyle of people [2], [3], [4].

The alternation of the day and night circadian cycle is a very important regulator of a wide variety of physiological rhythms in living organisms, including humans [5], [6], [7]. Disruption of circadian rhythmicity reduced longevity in golden hamsters [8]. Several studies have reported a higher prevalence of coronary risk factors among rotating shift workers, including increasing cigarette consumption, higher blood pressure and increased serum cholesterol, glucose and uric acid levels and urinary adrenaline excretion [9], [10], [11] and coronary heart disease risk in them [12]. Permanent night workers had increased risk of psychiatric disturbances [13]. It was shown that desynchronization of light regimen potentiated ulcerative processes in the rat stomach [14]. Due to the introduction of electricity and artificial light ≈100 years ago, the pattern and duration of human exposure to light has changed dramatically and thus light-at-night has become an increasing and essential part of modern lifestyle. Light exposure at night seems associated with a number of serious behavioral as well as health problems, including cancer. An exposure to constant light (24 h a day, LL) was followed by a shortening of life span in the fruit fly [15], [16]. In rodents, the light-at-night leads to disruption of the ovulatory cycle [17], [18], [19], [20], followed by hyperplastic processes in mammary gland, ovarian and uterine tumor development [21], [22], [23], [24]. Also shown was the tumor-promoting effect of exposure to the LL regimen on mammary gland carcinogenesis in mice and rats [4], [25], [26], [27]. Normal breast exhibits rhythmic properties linked to the hormonal environment of the gland in animals and humans, whereas breast cancer in humans is characterized by disruption or modification of normal circadian patterns, which may be of prognostic value [28].

Prolonged light exposure suppresses the night peak release of melatonin—the ‘hormone of the night’ in rodents and in human [4], [5], [27], [29], [30], [31], [32]. It was shown under highly controlled exposure circumstances, <1 lux of monochromatic light elicited a significant suppression of nocturnal melatonin [33]. Melatonin is a principal hormone of the pineal gland—the small neuroendocrine gland connected with the brain which mediates information on light from the retina of the eyes to the organism [5], [34].

Recently, the Journal of the National Cancer Institute [35], [36] published two papers reporting a significant increase in the risk of breast cancer among women who frequently did not sleep during the period of the night, ≈01:30 h, when melatonin levels are typically at their highest. There was increased risk among women sleeping in the brightest bedrooms. Moreover, women who had worked 30 and more years on rotating night shifts had a 36% greater risk of breast cancer compared with workers who had never worked nights. Earlier, epidemiologists had shown an elevated breast cancer risk among post-menopausal radio and telegraph operators exposed to shift work as well as among flight attendants working markedly random night periods [37], [38], [39], [40]. ‘Melatonin hypothesis’ suggests that reduced pineal melatonin production might increase human breast cancer risk because a lower melatonin output would lead to an increase in the level of female sex hormones and would stimulate proliferation of breast tissue [3], [41], [42]. However, the exact mechanisms of the connection of melatonin inadequacy with breast cancer have not been well explored. In the present paper, available data on the role of a modulation of the pineal function by light/dark regimen in breast cancer development are discussed.

Section snippets

Effect of constant light regimen on spontaneous mammary carcinogenesis

An artificial increase the length of light phase of the day (by 2–4 h) is usually followed by the increase in the duration of estral cycle and in some cases to its disturbance in rodents. In the complete absence of a light–dark alternation, in constant light (24 h a day, LL), the rat and mouse go into a state of persistent estrus fairly soon after exposure to constant light [17], [18], [19], [20]. In physiological circumstances, this syndrome naturally develops in aged animals (in rats, between

Effect of constant light regimen on chemically-induced mammary carcinogenesis

In 1965, Khaetsky [52] first reported a modifying effect of exposure to the LL regimen on 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis in rats. Female rats were kept at standard LD regimen or at the LL regimen during 7 weeks and then were exposed to DMBA mammary tumors developed in 40% of LD and in 29% of LL rats. Granulesa-cell ovarian tumors developed in 24% of the LL rats, but not in the LD group. In another set of experiments, female rats were injected with DMBA and

Effect of light deprivation on mammary carcinogenesis

Kuralasov [67], [68] firstly studied the effect of light deprivation on growth and development of transplantable and DMBA-induced mammary tumors. Animals were kept in dark room (0–0.5 lux/cm2) (DD) or under standard light-dark regimen (LD). The transplantability of rat RMK-1 mammary carcinoma was 89.5% in rats kept at the LD regimen and only 58.6% in rats under the DD regimen (P<0.05). The mean doubling time of the tumor growth was 82.3 h in the LD group and 138 h in the DD group.

Effect of melatonin on mammary tumor development

The evidence of oncostatic action of melatonin on mammary tumor growth was obtained both in vitro and in vivo experiments. MCF-7 human breast cancer cell line is commonly used model for study of melatonin effect in vitro [76], [77]. This cell lines originated from the pleural effusion of woman with metastatic breast carcinoma and contains both estrogen and progesterone receptors. It was shown that a growth of MCF-7 cells is estrogen dependent and estrogens regulate the levels of some RNAs and

Mechanisms of anti-carcinogenic effects of melatonin

The nocturnal plasma melatonin was found to be significantly depressed both 2 and 7 days after the DMBA administration into rats, whereas the main metabolite of melatonin, 6-sulfatoxymelatonin (aMT6s), did not differ compared to controls, indicating an increased degradation of the pineal hormone due to DMBA [106], [107]. It was shown that 6-hydroxylation of melatonin by hepatic microsomal monoxygenases of the cytochrome P450 system are also enhanced by DMBA treatment [108].

Comprehensive review

Effect of pineal peptides on mammary carcinogenesis

Most investigators invoked melatonin as a primary mediator of the endocrine functions of the pineal gland. However, some of the effects of the pineal gland obviously might have resulted from pineal peptide secretion [135]. Some crude peptide extracts or purified peptides isolated from pineal glands were shown to have antigonadotropic, metabolic, and antitumor activity [136], [137], [138], [139], [140]. Epithalamin® is a low molecular weight peptide preparation containing a complex of

Mechanisms of anti-carcinogenic effects of pineal peptides

The data on biological activities of pineal peptide preparation Epithalamin has been reviewed recently [141], [142]. It was shown that Epithalamin increases pineal synthesis of serotonin, N-acetylserotonin and melatonin and night pineal secretion of melatonin in adult and old rats. The preparation decreases the LH and prolactin levels in rats as well as the threshold of the hypothalamo-pituitary complex to feedback inhibition by estrogens in old female rats; Epithalamin increases the levels of

Conclusion

Data reviewed show the important role of the pineal gland in development of breast cancer. Inhibition of pineal function with the pinealectomy or with exposure to the constant light regimen stimulates mammary carcinogenesis, whereas a light deprivation inhibits the carcinogenesis. Epidemiological observations on increased risk of breast cancer in night shift workers, flight attendants, radio and telegraph operators and on the decreased risk in blind women are in accordance with the results of

Reviewers

Professor Christian Bartsch. Centre for Research in Medical and Natural Sciences, University of Tübingen, Ob dem Himmelreich 7, D-72074 Tübingen, Germany.

Dr David E. Blask. Laboratory of Experimental Neuroendocrinology/Oncology, The Mary Imogene Bassett Research Institute, One Atwell Road, Cooperstown, NY 13326-1394, USA.

Professor Frank L. Meyskens. University of California, Irvine, CHAO Family Comprehensive Cancer Center, 101 The City Drive South, Rt. 81, Building 23, Room 406, Orange, CA

Acknowledgements

The study was supported by Grants No. 99-04-48023 and 00-04-48481 from the Russian Foundation for Basic Research and by Grants No. 01-SC-NIH-1031 and 02-SC-NIH-1047 from Duke University, NC, USA.

Professor Vladimir N. Anisimov, MD, PhD, DSc, graduated from the First Leningrad Medical Institute in 1968 and received his PhD (1972) and DSc (1984) degrees from the N.N. Petrov Research Institute of Oncology (St. Petersburg). In 1996, he was elected as an associate member of the Russian Academy of Natural Sciences. Since 1987, he has been Chief of the Laboratory of Carcinogenesis and Aging at the Petrov’ Institute and in addition, since 1998, Head of the Department of Carcinogenesis and

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    Professor Vladimir N. Anisimov, MD, PhD, DSc, graduated from the First Leningrad Medical Institute in 1968 and received his PhD (1972) and DSc (1984) degrees from the N.N. Petrov Research Institute of Oncology (St. Petersburg). In 1996, he was elected as an associate member of the Russian Academy of Natural Sciences. Since 1987, he has been Chief of the Laboratory of Carcinogenesis and Aging at the Petrov’ Institute and in addition, since 1998, Head of the Department of Carcinogenesis and Oncogerontology at the same institute. Since 1999, he is also Scientific Director, St. Petersburg Institute of Bioregulation and Gerontology, North-Western Branch of the Russian Academy of Medical Sciences. Professor Anisimov's main scientific interests are the relationship between aging and cancer, the modifying factors of carcinogenesis, experimental gerontology and the role of pineal gland in cancer and aging. He is a member of a number of scientific societies and is on the editorial board of several international journals. Since 1994, he is the president of the Gerontological Society of the Russian Academy of Sciences. Professor Anisimov is author and co-author of 12 monographs, including ‘Carcinogenesis and Aging’, vols. 1 and 2, CRC Press, Boca Raton (1987), ‘Principles for Evaluating Chemical Effects on the Aged Population. Environmental Health Criteria 144’, WHO, Geneva (1993) and ‘Evolution of Concepts in Gerontology’, Aesculap, St. Petersburg (1999), a number of chapters in books, more than 320 scientific papers in peer-reviewed international and Russian journals.

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