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Switch Off Cancer aims to educate people how to have healthy, functioning pineal glands with ‘normal’ melatonin flow in order to prevent and help treat cancer.

Melatonin and other anticancer agents are released every night by the pineal gland, after dark. Blue light wavelengths in artificial white light surpress its production.

We have evolved over millenia to a rhythmic light dark cycle, spending half our time in the bright daylight and the other half in the dark. In our modern world we now spend most of the day indoors and illuminate our nights with artificial light.

Video: Dr. Russel Reiter PhD on nighttime light and cancer risks

Dr. Russel Reiter PhD discusses blue component in nighttime light, supression of melatonin production and the risks of certain cancers because of it.

Video courtesy of YouTube:

http://youtu.be/sJCwIU6Z1W4

Functional interplay between melatonin receptor-mediated antiproliferative signaling and androgen receptor signaling in human prostate epithelial cells: potential implications for therapeutic strategies against prostate cancer.

J Pineal Res. 2011 Apr 2. doi: 10.1111/j.1600-079X.2011.00888.x. [Epub ahead of print]
Blask DE, Hill SM, Dauchy RT, Xiang S, Yuan L, Duplessis T, Mao L, Dauchy E, Sauer LA.
Circadian regulation of molecular, dietary, and metabolic signaling mechanisms of human breast cancer growth by the nocturnal melatonin signal and the consequences of its disruption by light at night.
Source
Laboratory of Chrono-Neuroendocrine Oncology Department of Structural and Cellular Biology, Tulane University School of Medicine Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA.

Abstract

This review article discusses recent work on the melatonin-mediated circadian regulation and integration of molecular, dietary, and metabolic signaling mechanisms involved in human breast cancer growth and the consequences of circadian disruption by exposure to light at night (LAN). The antiproliferative effects of the circadian melatonin signal are mediated through a major mechanism involving the activation of MT(1) melatonin receptors expressed in human breast cancer cell lines and xenografts. In estrogen receptor (ERá+) human breast cancer cells, melatonin suppresses both ERá mRNA expression and estrogen-induced transcriptional activity of the ERá via MT(1) -induced activation of G(ái2) signaling and reduction of 3`,5`-cyclic adenosine monophosphate (cAMP) levels. Melatonin also regulates the transactivation of additional members of the steroid hormone/nuclear receptor super-family, enzymes involved in estrogen metabolism, expression/activation of telomerase, and the expression of core clock and clock-related genes. The anti-invasive/anti-metastatic actions of melatonin involve the blockade of p38 phosphorylation and the expression of matrix metalloproteinases. Melatonin also inhibits the growth of human breast cancer xenografts via another critical pathway involving MT(1) -mediated suppression of cAMP leading to blockade of linoleic acid uptake and its metabolism to the mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13-HODE). Down-regulation of 13-HODE reduces the activation of growth factor pathways supporting cell proliferation and survival. Experimental evidence in rats and humans indicating that LAN-induced circadian disruption of the nocturnal melatonin signal activates human breast cancer growth, metabolism, and signaling provides the strongest mechanistic support, thus far, for population and ecological studies demonstrating elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LAN.

© 2011 John Wiley & Sons A/S.

Circadian regulation of molecular, dietary, and metabolic signaling mechanisms of human breast cancer growth by the nocturnal melatonin signal and the consequences of its disruption by light at night.

J Pineal Res. 2011 Apr 2. doi: 10.1111/j.1600-079X.2011.00888.x. [Epub ahead of print]
Blask DE, Hill SM, Dauchy RT, Xiang S, Yuan L, Duplessis T, Mao L, Dauchy E, Sauer LA.
Circadian regulation of molecular, dietary, and metabolic signaling mechanisms of human breast cancer growth by the nocturnal melatonin signal and the consequences of its disruption by light at night.
Source
Laboratory of Chrono-Neuroendocrine Oncology Department of Structural and Cellular Biology, Tulane University School of Medicine Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA.

Abstract

This review article discusses recent work on the melatonin-mediated circadian regulation and integration of molecular, dietary, and metabolic signaling mechanisms involved in human breast cancer growth and the consequences of circadian disruption by exposure to light at night (LAN). The antiproliferative effects of the circadian melatonin signal are mediated through a major mechanism involving the activation of MT(1) melatonin receptors expressed in human breast cancer cell lines and xenografts. In estrogen receptor (ERá+) human breast cancer cells, melatonin suppresses both ERá mRNA expression and estrogen-induced transcriptional activity of the ERá via MT(1) -induced activation of G(ái2) signaling and reduction of 3`,5`-cyclic adenosine monophosphate (cAMP) levels. Melatonin also regulates the transactivation of additional members of the steroid hormone/nuclear receptor super-family, enzymes involved in estrogen metabolism, expression/activation of telomerase, and the expression of core clock and clock-related genes. The anti-invasive/anti-metastatic actions of melatonin involve the blockade of p38 phosphorylation and the expression of matrix metalloproteinases. Melatonin also inhibits the growth of human breast cancer xenografts via another critical pathway involving MT(1) -mediated suppression of cAMP leading to blockade of linoleic acid uptake and its metabolism to the mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13-HODE). Down-regulation of 13-HODE reduces the activation of growth factor pathways supporting cell proliferation and survival. Experimental evidence in rats and humans indicating that LAN-induced circadian disruption of the nocturnal melatonin signal activates human breast cancer growth, metabolism, and signaling provides the strongest mechanistic support, thus far, for population and ecological studies demonstrating elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LAN.

© 2011 John Wiley & Sons A/S.

Melatonin reduces pancreatic tumor cell viability by altering mitochondrial physiology.

Authors:
Gonzalez, Antonio1
del Castillo-Vaquero, Angel1
Miro-Moran, Alvaro1
Tapia, Jose A.1
Salido, Gines M.1
Source:
Journal of Pineal Research; Apr2011, Vol. 50 Issue 3, p250-260, 11p
Document Type:
Article
Subject Terms:
*MELATONIN
*CANCER cells
*PANCREAS — Tumors
*MITOCHONDRIA
*PHYSIOLOGY
*CELL proliferation
*CELL lines
*ANTINEOPLASTIC agents
*APOPTOSIS

Abstract:
Melatonin reduces proliferation in many different cancer cell lines. Thus, melatonin is considered a promising antitumor agent, promoting apoptosis in tumor cells while preserving viability of normal cells. Herein, we examined the effects of melatonin on the pancreatic AR42J tumor cell line. We have analyzed cytosolic-free Ca concentration ([Ca]), mitochondrial-free Ca concentration ([Ca]), mitochondrial membrane potential (Øm), mitochondrial flavin adenine dinucleotide (FAD) oxidative state, cellular viability and caspase-3 activity. Our results show that melatonin induced transient changes in [Ca] and [Ca]. Melatonin also induced depolarization of Øm and led to a reduction in the level of oxidized FAD. In addition, melatonin reduced AR42J cell viability. Finally, we found a Ca-dependent caspase-3 activation in response to melatonin. Collectively, these data support the likelihood that melatonin reduces viability of tumor AR42J cells via its action on mitochondrial activity and caspase-3 activation. [ABSTRACT FROM AUTHOR]
Author Affiliations:
1Department of Physiology, Cell Physiology Research Group, University of Extremadura, Caceres, Spain

Does the modern urbanized sleeping habitat pose a breast cancer risk?

Chronobiol Int. 2011 Feb;28(1):76-80.
Does the modern urbanized sleeping habitat pose a breast cancer risk?

Kloog I, Portnov BA, Rennert HS, Haim A.

Department of Natural Resources and Environmental Management, Graduate School of Management, University of Haifa, Haifa, Israel.

Abstract

Due to its disruptive effects on circadian rhythms and sleep deprivation at night, shiftworking is currently recognized as a risk factor for breast cancer (BC). As revealed by the present analysis based on a comparative case-control study of 1679 women, exposure to light-at-night (LAN) in the “sleeping habitat” is significantly associated with BC risk

(odds ratio [OR] = 1.220, 95% confidence interval [CI]= 1.118-1.311; p < .001), controlling for education, ethnicity, fertility, and alcohol consumption. The novelty of the present research is that, to the best of the authors` knowledge, it is the first study to have identified an unequivocal positive association between bedroom-light intensity and BC risk. Thus, according to the results of the present study, not only should artificial light exposure in the working environment be considered as a potential risk factor for BC, but also LAN in the “sleeping habitat.”

Shift work, light at night, and the risk of breast cancer.

Authors:
Reed, Virginia A
Source: AAOHN Journal (AAOHN J), 2011 Jan; 59(1): 37-47 (142 ref)
Publication Type: journal article – CEU, exam questions, review
Language: English
Major Subjects:
Breast Neoplasms — Risk Factors
Circadian Rhythm
Harm Reduction
Hospital Policies
Light — Adverse Effects
Occupational Health Nursing
Occupational Safety
Personnel Staffing and Scheduling — Methods
Shift Workers
Shiftwork
Minor Subjects:
Education, Continuing (Credit); Environmental Health; Melatonin — Physiology; Occupational Exposure; Research; Risk Factors
Abstract:
Studies of the effect of shift work have identified several negative health outcomes, most notably breast cancer. Disruption of circadian rhythm by exposure to light at night has been identified as the mechanism likely responsible for this outcome. This article recommends that health care institutions work with occupational health nurses to develop and implement hazard communication and policies concerning shift work, exposure to light at night, and increased risk for negative health outcomes, particularly breast cancer.
Journal Subset:
Blind Peer Reviewed; Core Nursing; Editorial Board Reviewed; Expert Peer Reviewed; Nursing; Peer Reviewed; USA

Light at night and breast cancer risk: results from a population-based case-control study in Connecticut, USA.

Cancer Causes Control. 2010 Dec;21(12):2281-5. Epub 2010 Oct 7.
Light at night and breast cancer risk: results from a population-based case-control study in Connecticut, USA.

Li Q, Zheng T, Holford TR, Boyle P, Zhang Y, Dai M.
Department of Social Medicine, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract

OBJECTIVE: To investigate the potential association between domestic exposure to light at night (LAN) and the risk of human breast cancer.
METHODS: A case-control study of female breast cancer was conducted in Connecticut. A total of 363 incident breast cancer cases and 356 age frequency-matched controls were interviewed using a standardized, structured questionnaire to obtain information on sleeping patterns and bedroom light environment. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional multivariate logistic regression.
RESULTS: A non-significantly increased risk of breast cancer was observed among postmenopausal women for those keeping lights on while sleeping (OR = 1.4, 95% CI 0.7, 2.7), those who reported mainly sleeping in the daytime (OR = 1.4, 95% CI 0.5, 4.3), and those not drawing the curtains/window shades while sleeping at night (OR = 1.2, 95% CI 0.8, 1.9).
CONCLUSION: The results from this study suggest a potential increased risk of breast cancer associated with domestic exposure to LAN. Further studies with larger sample size are needed to confirm the results.

'Lights out' may help fight cancer

United Press International

04-13-10

Lamplight burning all night may affect cell division and increase the risk of cancer, Israeli and British researchers warn.

Study leaders Dr. Rachel Ben-Shlomo of the University of Haifa in Israel and Charalambos Kyriacou of the University of Leicester in England said just one “pulse” of artificial light during night hours was enough to disrupt the body`s circadian “clock” and affect how the body`s cells divided.

“Damage to cell division is characteristic of cancer, and is therefore important to understand the causes of this damage,” Ben-Shlomo said in a statement.

Ben-Shlomo, Kyriacou and colleagues exposed laboratory mice to 12 hours of light and 12 hours of darkness. During the dark hours, one group of mice was exposed to artificial light for one hour.

The mice studies, published in the journal Cancer Genetics and Cytogenetics, link exposure to the un-natural light to changes in the biological clocks of the cells — which affected genes that control how cells form cancer as well as how cells fight against cancer.

“What is certain is that the natural division is affected,” Ben-Shlomo said.

Articles featured in Life Extension Daily News are derived from a variety of news sources and are provided as a service by Life Extension. These articles, while of potential interest to readers of Life Extension Daily News, do not necessarily represent the opinions nor constitute the advice of Life Extension.

Circadian Stage-Dependent Inhibition of Human Breast Cancer Metabolism and Growth by the Nocturnal Melatonin Signal: Consequences of Its Disruption by Light at Night in Rats and Women

Blask, David E.(1); Dauchy, Robert T.(2); Brainard, George C.(3); Hanifin, John P.(3)

  1. Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University School of Medicine, New Orleans, LA, USA, dblask@tulane.edu
  2. Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University School of Medicine, New Orleans, LA, USA
  3. Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA

The circadian production of melatonin by the pineal gland during the night provides an inhibitory signal to tissue-isolated steroid receptor SR+ and — MCF-7 human breast cancer xenografts in female nude rats. A pivotal mechanism for melatonin’s anticancer effects in vivo involves a melatonin receptor-mediated inhibition of linoleic acid (LA) uptake and its metabolism to mitogenically active 13-hydroxyoctadecadienoic acid (13-HODE). Exposure of (SR-) xenograft-bearing rats to increasing intensities of polychromatic white light at night suppresses melatonin while increasing tumor growth rates, DNA content, [3H]thymidine incorporation into DNA, LA uptake, 13-HODE formation, cAMP levels and ERK1/2 activation a dose-dependent manner. Similar effects occur in SR- human breast cancer xenografts perfused in situ with melatonin-depleted blood from healthy female subjects after their exposure to a single bright intensity (2800 lux) of polychromatic light at night. Additionally, SR- human breast cancer xenografts exhibit robust circadian rhythms of LA uptake, 13-HODE formation and proliferative activity. Exposure of xenograft-bearing rats to dim light at night results in the complete elimination of these rhythms which culminates in unfettered, high rates of tumor metabolism and growth. The organization of tumor metabolism and growth within circadian time structure by the oncostatic melatonin signal helps create a balance between the cancer and its host that is disrupted by host exposure to light at night. This biological mechanism may partially explain the higher risk of breast and other cancers in women working rotating night shifts and possibly others who also experience prolonged exposure to light at night.

Total visual blindness is protective against breast cancer

Cancer Causes Control. 2009 Aug 1. [Epub ahead of print]
Total visual blindness is protective against breast cancer.Flynn-Evans EE, Stevens RG, Tabandeh H, Schernhammer ES, Lockley SW.
Division of Sleep Medicine, Brigham and Women`s Hospital, 221 Longwood Avenue BLI 438, Boston, MA, 02115, USA, eevans@rics.bwh.harvard.edu.

OBJECTIVE: Observational data, though sparse and based on small studies with limited ability to control for known breast cancer risk factors, support a lower risk of breast cancer in blind women compared to sighted women. Mechanisms influenced by ocular light perception, such as melatonin or circadian synchronization, are thought to account for this lower risk. METHODS: To evaluate whether blind women with no perception of light (NPL) have a lower prevalence of breast cancer compared to blind women with light perception (LP), we surveyed a cohort of 1,392 blind women living in North America (66 breast cancer cases). RESULTS: In multivariate-logistic regression models controlling for breast cancer risk factors, women with NPL had a significantly lower prevalence of breast cancer than women with LP (odds ratio, 0.43; 95% confidence interval, 0.21-0.85). We observed little difference in these associations when restricting to postmenopausal women, non-shift workers or when excluding women diagnosed with breast cancer within 2 or 4 years of onset of blindness. Blind women with NPL appear to have a lower risk of breast cancer, compared to blind women with LP. More research is needed to elucidate the impact of LP on circadian coordination and melatonin production in the blind and how these factors may relate to breast cancer risk.

PMID: 19649715

Nighttime use of special spectacles or light bulbs that block blue light may reduce the risk of cancer

Medical Hypotheses 73 (2009) 324–325

Nighttime use of special spectacles or light bulbs that block

blue light may reduce the risk of cancer

Martin Alpert, Edward Carome, Vilnis Kubulins, Richard Hansler

*
Lighting Innovations Institute, John Carroll University, 20700 North Park Blvd., University Heights, OH 44118, United States

Article Info

Article history:

Received 18 February 2009

Accepted 21 February 2009

Summary

For more than 15 years evidence has been accumulating that there is a link between a lack of melatonin and cancer, especially breast, ovarian and prostate cancer. For a similar period it has been known that exposing the eyes to light when melatonin is normally flowing reduces or eliminates the flow. What is relatively new is that it is primarily the blue wavelengths that are responsible for loss of melatonin. Blocking these blue rays with amber glasses restores melatonin flow. Also new is the direct evidence, from analysis of the famous nurses’ health study, that having more melatonin present in first morning urine is linked to a reduction in the incidence of breast cancer. This leads to the hypothesis that wearing amber glasses (or using blue-free light bulbs) for a few hours before bedtime maximizes melatonin production and reduces the risk of breast, ovarian and prostate cancer and possibly other cancers.

2009 Elsevier Ltd. All rights reserved.

Light, melatonin and cancer: current results and future perspectives.

Light, melatonin and cancer: current results and future perspectives.
Authors:
Bartsch, Christian(1) christian.bartsch@uni-tuebingen.de
Bartsch, Hella(1)
Peschke, Elmar(2)
Source:
Biological Rhythm Research Feb2009, Vol. 40 Issue 1, p17 19p.
Language:
English
Subject Terms:
*MELATONIN
*CANCER
*CIRCADIAN rhythms
*TUMORS
LIGHT
Abstract:
The article discusses the study on the effects and future perspectives of light, melatonin and cancer. It states that nocturnal light affects the production of pineal melatonin which possesses anti-carcinogenic properties and triggers the slow growth of well-differentiated experimental tumours. It adds that circadian rhythm disturbances and lights at night can enhance cancer- causing effects.
Author Affiliations:
1 Center for Research in Medical and Natural Sciences, University of Tübingen, Tübingen, Germany; 2 Department of Anatomy and Cell Biology, Medical Faculty, University of Halle-Wittenberg, Halle, Germany

Therapeutic actions of melatonin in cancer: possible mechanisms.

Therapeutic actions of melatonin in cancer: possible mechanisms.
Srinivasan V, Spence DW, Pandi-Perumal SR, Trakht I, Cardinali DP.
Department of Physiology, School of Medical Sciences, University Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.

Melatonin is a phylogenetically well-preserved molecule with diverse physiological functions. In addition to its well-known regulatory control of the sleep/wake cycle, as well as circadian rhythms generally, melatonin is involved in immunomodulation, hematopoiesis, and antioxidative processes. Recent human and animal studies have now shown that melatonin also has important oncostatic properties. Both at physiological and pharmacological doses melatonin exerts growth inhibitory effects on breast cancer cell lines. In hepatomas, through its activation of MT1 and MT2 receptors, melatonin inhibits linoleic acid uptake, thereby preventing the formation of the mitogenic metabolite 1,3-hydroxyoctadecadienoic acid. In animal model studies, melatonin has been shown to have preventative action against nitrosodiethylamine (NDEA)-induced liver cancer. Melatonin also inhibits the growth of prostate tumors via activation of MT1 receptors thereby inducing translocation of the androgen receptor to the cytoplasm and inhibition of the effect of endogenous androgens. There is abundant evidence indicating that melatonin is involved in preventing tumor initiation, promotion, and progression. The anticarcinogenic effect of melatonin on neoplastic cells relies on its antioxidant, immunostimulating, and apoptotic properties. Melatonin`s oncostatic actions include the direct augmentation of natural killer (NK) cell activity, which increases immunosurveillance, as well as the stimulation of cytokine production, for example, of interleukin (IL)-2, IL-6, IL-12, and interferon (IFN)-gamma. In addition to its direct oncostatic action, melatonin protects hematopoietic precursors from the toxic effect of anticancer chemotherapeutic drugs. Melatonin secretion is impaired in patients suffering from breast cancer, endometrial cancer, or colorectal cancer. The increased incidence of breast cancer and colorectal cancer seen in nurses and other night shift workers suggests a possible link between diminished secretion of melatonin and increased exposure to light during nighttime. The physiological surge of melatonin at night is thus considered a “natural restraint” on tumor initiation, promotion, and progression.
PMID: 18815150 [PubMed – in process]

Sleep duration, melatonin and breast cancer among Chinese women in Singapore.

Carcinogenesis. 2008 Jun;29(6):1244-8. Epub 2008 Apr 30.

Sleep duration, melatonin and breast cancer among Chinese women in Singapore.

Wu AH, Wang R, Koh WP, Stanczyk FZ, Lee HP, Yu MC.
Department of Preventive Medicine, University of Southern California Keck School of Medicine, 1441 Eastlake Avenue, Los Angeles, CA 90089, USA. annawu@usc.edu

BACKGROUND: Sleep duration has been hypothesized to be inversely associated with breast cancer risk, possibly due to greater overall melatonin production in longer sleepers. However, data are inconclusive from the three studies conducted in Western populations on sleep duration and breast cancer risk. METHODS: We investigated the relationship between self-reported usual sleep duration determined at baseline and subsequent risk of breast cancer in the prospective, population-based cohort of the Singapore Chinese Health Study. We excluded from the study women with <2 years of follow-up due to possible change in sleep pattern among breast cancer cases close to the time of diagnosis. Five hundred and twenty-five incident cases of breast cancer were identified among the remaining 33 528 women after up to 11 years of follow-up. RESULTS: Among women postmenopausal at baseline, breast cancer risk decreased with increasing sleep duration (P trend = 0.047); those who reported 9+ h of sleep showed a relative risk of 0.67 (95% confidence interval = 0.4-1.1) compared with women who reported < or =6 h of sleep. This inverse association was observed primarily in lean women [i.e. body mass index below the median value (23.2 kg/m(2))] (P = 0.024). In this study population, irrespective of gender, urinary 6-sulfatoxymelatonin levels increased with increasing self-reported hours of sleep (P trend = 0.035) after adjustment for age and time of day of urine collection. Melatonin levels were 42% higher in those with 9+ versus those with < or =6 h of sleep. CONCLUSION: Sleep duration may influence breast cancer risk, possibly via its effect on melatonin levels.

Light at Night Co-distributes with Incident Breast but not Lung Cancer in the Female Population of Israel.

Authors:
Kloog, Itai(1)
Haim, Abraham(2)
Stevens, Richard G.(3)
Barchana, Micha(4,5)
Portnov, Boris A.(1) portnov@nrem.haifa.ac.il

Source:
Chronobiology International: The Journal of Biological & Medical Rhythm Research 2008, Vol. 25 Issue 1, p65 17p.

Language:
English

Subject Terms:
*LUNGS — Cancer
*BREAST — Cancer
*CANCER
*CHILDBIRTH
CANCER in women
MULTIPLE regression analysis
REGRESSION analysis
STATISTICS
POPULATION

Geographic Terms:
ISRAEL

Keyword(s):
Breast cancer; Light at night; Melatonin Lung cancer

Abstract:
Recent studies of shift-working women have reported that excessive exposure to light at night (LAN) may be a risk factor for breast cancer. However, no studies have yet attempted to examine the co-distribution of LAN and breast cancer incidence on a population level with the goal to assess the coherence of these earlier findings with population trends. Coherence is one of Hill`s “criteria” (actually, viewpoints) for an inference of causality. Nighttime satellite images were used to estimate LAN levels in 147 communities in Israel. Multiple regression analysis was performed to investigate the association between LAN and breast cancer incidence rates and, as a test of the specificity of our method, lung cancer incidence rates in women across localities under the prediction of a link with breast cancer but not lung cancer. After adjusting for several variables available on a population level, such as ethnic makeup, birth rate, population density, and local income level, a strong positive association between LAN intensity and breast cancer rate was revealed (p<0.05), and this association strengthened (p<0.01) when only statistically significant factors were filtered out by stepwise regression analysis. Concurrently, no association was found between LAN intensity and lung cancer rate. These results provide coherence of the previously reported case-control and cohort studies with the co-distribution of LAN and breast cancer on a population basis. The analysis yielded an estimated 73% higher breast cancer incidence in the highest LAN exposed communities compared to the lowest LAN exposed communities. ABSTRACT FROM AUTHOR

Author Affiliations:
1 Department of Natural Resources & Environmental Management, University of Haifa, Haifa, Israel.; 2 Department of Biology, University of Haifa-Oranim, Kiryat Tivon, Israel.; 3 University of Connecticut Health Center, Farmington, Connecticut, USA.; 4 School of Public Health, University of Haifa, Haifa.; 5 Israel National Cancer Registry, Ministry of Health, Jerusalem, Israel.

Breast cancer and night work among Norwegian nurses.

Cancer Causes Control. 2006 Feb;17(1):39-44.

Breast cancer and night work among Norwegian nurses.

Lie JA, Roessink J, Kjaerheim K.

Cancer Registry of Norway, Institute of Population-based Cancer Research, N-0310, Oslo, Montebello, Norway. jasl@kreftregisteret.no

OBJECTIVE: Previous studies have suggested an association between breast cancer and night work. We evaluated the relationship among Norwegian nurses. METHODS: A case-control study, nested within a cohort of 44,835 nurses educated between 1914 and 1980 was performed, based on a registry of all Norwegian nurses. Four controls were individually matched by year of birth to each of 537 breast cancer cases that occurred during the period 1960-1982. The reconstruction of work history and number of years with night work for each nurse was based on information from the nurse registry, and data from three censuses. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for total duration of work as a nurse and parity. All statistical tests were two-sided. RESULTS: The adjusted OR of breast cancer among nurses who worked nights for 30 or more years was 2.21 (CI 1.10-4.45) compared with those who did not work nights after graduation from nursing school (p(trend) = 0.01). CONCLUSION: Our results are in accordance with previous studies that find an association between night work and breast cancer risk among women.

Exposure To Light At Night Increases The Growth Of DMBA-Induced Mammary Adenocarcinomas In Rats

Exposure to light-at-night increases the growth of DMBA-induced mammary adenocarcinomas in rats.

Cos S, Mediavilla D, Martinez-Campa C, Gonzalez A, Alonso-Gonzalez C, Sanchez-Barcelo EJ.

Department of Physiology and Pharmacology, School of Medicine, University of Cantabria, 39011 Santander, Spain.

In order to assess whether light exposure at night influences the growth of mammary tumors, as well as the role of melatonin in this process, female rats bearing DMBA-induced mammary adenocarcinomas were exposed to different lighting environments. Animals exposed to light-at-night, especially those under a constant dim light during the darkness phase, showed: (a) significantly higher rates of tumor growth as well as lower survival than controls, (b) higher concentration of serum estradiol, and (c) lower nocturnal excretion of 6-sulfatoxymelatonin, without there being differences between nocturnal and diurnal levels. These results suggest that circadian and endocrine disruption induced by light pollution, could induce the growth of mammary tumors.

Blocking low-wavelength light prevents nocturnal melatonin suppression with no adverse effect on performance during simulated shift work.

J Clin Endocrinol Metab. 2005 May;90(5):2755-61. Epub 2005 Feb 15.

Blocking low-wavelength light prevents nocturnal melatonin suppression with no adverse effect on performance during simulated shift work.
Kayumov L, Casper RF, Hawa RJ, Perelman B, Chung SA, Sokalsky S, Shapiro CM.

Sleep Research Laboratory, Department of Psychiatry, University Health Network, ECW 3D-035, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8. lkayumov@uhnres.utoronto.ca

Decreases in melatonin production in human and animals are known to be caused by environmental lighting, especially short-wavelength lighting (between 470 and 525 nm). We investigated the novel hypothesis that the use of goggles with selective exclusion of all wavelengths less than 530 nm could prevent the suppression of melatonin in bright-light conditions during a simulated shift-work experiment. Salivary melatonin levels were measured under dim (<5 lux), bright (800 lux), and filtered (800 lux) light at hourly intervals between 2000 and 0800 h in 11 healthy young males and eight females (mean age, 24.7 +/- 4.6 yr). The measurements were performed during three nonconsecutive nights over a 2-wk period. Subjective sleepiness was measured by self-report scales, whereas objective performance was assessed with the Continuous Performance Test. All subjects demonstrated preserved melatonin levels in filtered light similar to their dim-light secretion profile. Unfiltered bright light drastically suppressed melatonin production. Normalization of endogenous melatonin production while wearing goggles did not impair measures of performance, subjective sleepiness, or alertness.

Melatonin-Estrogen Interactions in Breast Cancer

J Pineal Res. 2005 May;38(4):217-22

Melatonin-estrogen interactions in breast cancer.

Sanchez-Barcelo EJ, Cos S, Mediavilla D, Martinez-Campa C, Gonzalez A, Alonso-Gonzalez C.

Department of Physiology and Pharmacology, School of Medicine, University of Cantabria, Santander, Spain. barcelo@unican.es

In this article, we review the experimental data supporting an oncostatic role of melatonin on hormone-dependent mammary tumors. Beginning with the evidence on the role of estrogens in breast cancer etiology and mammary tumor growth, we summarize the actual therapeutic strategies with estrogens as a target. Additionally, we demonstrate that melatonin fulfills all the requirements to be considered as an antiestrogenic drug which shares properties with drugs of the two main pharmacological groups of substances which interact with the estrogen-signaling pathways such as: (i) drugs that act through the estrogen receptor interfering with the effects of endogenous estrogens; and (ii) drugs that interfere with the synthesis of estrogens by inhibiting the enzymes controlling the interconversion from their androgenic precursors. Furthermore, melatonin decreases circulating levels of estradiol. These three antiestrogenic mechanisms suggest that melatonin may have an important role in the prevention and treatment of hormone-dependent mammary cancer.

Circadian disruption and breast cancer: from melatonin to clock genes.

Epidemiology. 2005 Mar;16(2):254-8.

Circadian disruption and breast cancer: from melatonin to clock genes.
Stevens RG.

Department of Community Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030-6325, USA. bugs@neuron.uchc.edu

The global impact of breast cancer is large and growing. It seems clear that something about modern life is the culprit, yet there is thus far a lack of satisfactory explanations for most of the increases in risk as societies industrialize. Support has developed for a possible role of “circadian disruption,” particularly from an altered-lighted environment (such as light at night). Lighting during the night of sufficient intensity can disrupt circadian rhythms, including reduction of circulating melatonin levels and resetting of the circadian pacemaker of the suprachiasmatic nuclei. Reduced melatonin may increase breast cancer risk through several mechanisms, including increased estrogen production and altered estrogen receptor function. The genes that drive the circadian rhythm are emerging as central players in gene regulation throughout the organism, particularly for cell-cycle regulatory genes and the genes of apoptosis. Aspects of modern life that can disrupt circadian rhythms during the key developmental periods (eg, in utero and during adolescence) may be particularly harmful. Epidemiologic studies should consider gene and environment interactions such as circadian gene variants and shift work requirements on the job.

Could visible light contribute to the development of leukaemia and other cancers in children?

: Med Hypotheses. 2005;64(4):864-71.

Could visible light contribute to the development of leukaemia and other cancers in children?
Erren TC.

Institute and Policlinic for Occupational and Social Medicine, School of Medicine and Dentistry, University of Cologne, Joseph-Stelzmann-Str. 9, 50924 Koln, Lindenthal, Germany. tim.erren@uni-koeln.de

This paper suggests to rigorously test the hypothesis that there are causal links between visible light and the development of leukaemia and other cancers in children. Light can be considered as a candidate risk factor because it suppresses melatonin biosynthesis which may play a role in a series of anticancer defences. Indeed, melatonin may offer some protection against all “hallmarks of cancer” [i.e., self-sufficiency in growth signals; insensitivity to growth-inhibitory signals; evasion of programmed cell death (apoptosis); limitless replicative potential; sustained angiogenesis; tissue invasion and metastasis] recently suggested by Hanahan and Weinberg. Already ongoing investigations into the possible nexus of light, endocrine systems and the development of cancers will be further fueled by recent insights into photoreception and — transduction, including the discovery of “novel” photoreceptors in the eye. Among a variety of different photosensory tasks, these receptors constitute crucial gates for light information from the environment which is employed for the temporal organization of our physiology and it has been proposed that chronodisruption, i.e., a significant disturbance of the coordination and thus order of biological rhythms, could contribute to the development of cancers. With regard to public health, the pervasive exposures to light — at work and in homes — imply that visible radiation could be a strong risk factor defined epidemiologically as a causal contributor to disease in a large proportion of cases. Importantly, if light were to be corroborated as a contributor to cancers in children, it would be amenable to manipulations with the perspective of reducing inherent risks significantly. In fact, it could be much easier — and much more effective — to reevaluate and modify lighting systems than to manipulate other possible determinants of the chronic processes of cancer such as genetic, nutritional or lifestyle factors.

The role of melatonin in the neurodegenerative diseases.

Bratisl Lek Listy. 2005;106(4-5):171-4.

The role of melatonin in the neurodegenerative diseases.

Olakowska E, Marcol W, Kotulska K, Lewin-Kowalik J.

Department of Physiology, Medical University of Silesia, Katowice, Poland.

Melatonin is a product of the pineal gland. Synthesis and release of this hormone is inhibited by light. The biological activity of melatonin is associated with its receptors–ML1 and ML2. Melatonin plays a role in the biologic regulation of circadian rhythms, sleep, mood, reproduction, tumor growth and aging. It may also modulate the activity of various receptors in cancer cells. The hormone is a free radical scavenger, an antioxidant and immunomodulatory agent. Antioxidant properties of melatonin are connected with its neuroprotective activity in several degenerative disorders. The etiology of the neurodegenerative diseases which are characterized by the progressive and irreversible destruction of specific neuronal populations is complex and multifactorial. One of causes of neurodegenerative damage in the nervous system is oxidative injury, which results from an inbalance between free radical formation and antioxidative mechanisms. The efficacy of melatonin in the inhibition of the oxidative stress was estimated in various neurodegenerative disorders whose pathogenesis is associated with cytotoxic activity of free oxygen radicals, such as Alzheimer`s or Parkinson`s disease. Melatonin may have a clinical potential for the treatment of neurodegenerative disorders in the central as well as peripheral nervous system. (Ref. 38.)

Light at night and cancer risk.

Photochem Photobiol. 2004 Apr;79(4):316-8.

Light at night and cancer risk.
Schernhammer E, Schulmeister K.

Channing Laboratory, Department of Medicine, Brigham and Women`s Hospital, Harvard Medical School, Boston, MA 02115, USA. eva.schernhammer@channing.harvard.edu

Environmental lighting powerfully suppresses the physiologic release of melatonin, which typically peaks in the middle of the night. This decreased melatonin production has been hypothesized to increase the risk of cancer. Evidence from experimental studies supports a link between melatonin and tumor growth. There is also fairly consistent indirect evidence from observational studies for an association between melatonin suppression, using night work as a surrogate, and breast cancer risk.

Melatonin and cancer risk: does light at night compromise physiologic cancer protection by lowering serum melatonin levels?

Br J Cancer. 2004 Mar 8;90(5):941-3.

Melatonin and cancer risk: does light at night compromise physiologic cancer protection by lowering serum melatonin levels?
Schernhammer ES, Schulmeister K.

Channing Laboratory, Department of Medicine, Brigham and Women`s Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA. eva.schernhammer@channing.harvard.edu

The suprachiasmatic nuclei in the hypothalamus, one of the most important physiological determinants of alertness and performance, drive a circadian pacemaker in mammals, with an intrinsic period averaging 24 h. Light is the primary stimulus to the disruption and resetting of this pacemaker, which is expressed in changing melatonin rhythms. Melatonin production in humans decreases when people are exposed to light at night. Since melatonin shows potential oncostatic action in a variety of tumours, it is possible that lowered serum melatonin levels caused by exposure to light at night enhance the general tumour development. Cancer is the second leading cause of death in industrialised countries like the United States, where a significant proportion of workers engage in shift work, making a hypothesised relation between light exposure at night and cancer risk relevant. Observational studies support an association between night work and cancer risk. We hypothesise that the potential primary culprit for this observed association is the lack of melatonin, a cancer-protective agent whose production is severely diminished in people exposed to light at night.

Spontaneous ovarian adenocarcinoma in the domestic turkey breeder hen (Meleagris gallopavo): effects of photoperiod and melatonin.

Neuro Endocrinol Lett. 2004 Feb-Apr;25(1-2):94-101.

Spontaneous ovarian adenocarcinoma in the domestic turkey breeder hen (Meleagris gallopavo): effects of photoperiod and melatonin.
Moore CB, Siopes TD.

Department of Poultry Science, North Carolina State University, Raleigh, North Carolina 27695-7608, USA. tom_siopes@ncsu.edu

OBJECTIVES: The effect of photoperiod or melatonin treatments on ovarian adenocarcinoma in turkey breeder hens (Meleagris gallopavo) was investigated to evaluate the usefulness of this animal as a model for studying ovarian cancer.

METHODS: In Experiment 1, photoperiod effects were tested by exposing turkeys with ovarian tumors to 8 wks of short days (8:16LD) followed by a 12 wk period of long days (16:8LD). In Experiment 2, exogenous melatonin was administered to turkeys during long day-induced development of ovarian tumors. In both experiments, the stage of tumor growth was scored weekly on a scale of 0 to 4.

RESULTS: It was clear that exposure to short days produced complete regression of tumors, with a mean time to score 0 of 4.4 wks. Following re-exposure to a long photoperiod, all of the same birds showed re-growth of the ovarian tumor with a mean time to first palpable detection of 5.4 wks. When melatonin was administered daily during the long photoperiod (Experiment 2), there was a significant delay in the re-growth of tumors.

CONCLUSION: It was clear from this study that the growth of solid ovarian tumors in the turkey breeder hen was promoted by long photoperiods and ceased, to the point of remission, on short photoperiods. Thus, ovarian adenocarcinoma in turkeys can be completely manipulated by photoperiod. In addition, treatment with melatonin attenuates tumor growth in the turkey hen. The results suggest that the domestic turkey hen is a useful in vivo model for studying spontaneous ovarian adenocarcinoma.

Lighting for the human circadian clock: recent research indicates that lighting has become a public health issue.

Med Hypotheses. 2004;63(4):588-96.

Lighting for the human circadian clock: recent research indicates that lighting has become a public health issue.
Pauley SM.
spauley@cox-internet.com

The hypothesis that the suppression of melatonin (MLT) by exposure to light at night (LAN) may be one reason for the higher rates of breast and colorectal cancers in the developed world deserves more attention. The literature supports raising this subject for awareness as a growing public health issue. Evidence now exists that indirectly links exposures to LAN to human breast and colorectal cancers in shift workers. The hypothesis begs an even larger question: has medical science overlooked the suppression of MLT by LAN as a contributor to the overall incidence of cancer? The indirect linkage of breast cancer to LAN is further supported by laboratory rat experiments by David E. Blask and colleagues. Experiments involved the implanting of human MCF-7 breast cancer cell xenografts into the groins of rats and measurements were made of cancer cell growth rates, the uptake of linoleic acid (LA), and MLT levels. One group of implanted rats were placed in light-dark (12L:12D) and a second group in light-light (12L:12L) environments. Constant light suppressed MLT, increased cancer cell growth rates, and increased LA uptake into cancer cells. The opposite was seen in the light-dark group. The proposed mechanism is the suppression of nocturnal MLT by exposure to LAN and subsequent lack of protection by MLT on cancer cell receptor sites which allows the uptake of LA which in turn enhances the growth of cancer cells. MLT is a protective, oncostatic hormone and strong antioxidant having evolved in all plants and animals over the millennia. In vertebrates, MLT is normally produced by the pineal gland during the early morning hours of darkness, even in nocturnal animals, and is suppressed by exposure to LAN. Daily entrainment of the human circadian clock is important for good human health. These studies suggest that the proper use and color of indoor and outdoor lighting is important to the health of both humans and ecosystems. Lighting fixtures should be designed to minimize interference with normal circadian rhythms in plants and animals. New discoveries on blue-light-sensitive retinal ganglion cell light receptors that control the circadian clock and how those receptors relate to today`s modern high intensity discharge (HID) lamps are discussed. There is a brief discussion of circadian rhythms and light pollution. With the precautionary principle in mind, practical suggestions are offered for better indoor and outdoor lighting practices designed to safeguard human health. Copyright 2004 Elsevier Ltd.

Melatonin and mammary cancer: a short review.

Endocr Relat Cancer. 2003 Jun;10(2):153-9.

Melatonin and mammary cancer: a short review.
Sanchez-Barcelo EJ, Cos S, Fernandez R, Mediavilla MD.

Department of Physiology and Pharmacology, School of Medicine, University of Cantabria, 39011 Santander, Spain. barcelo@unican.es

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.

The role of pineal gland in breast cancer development.

Crit Rev Oncol Hematol. 2003 Jun;46(3):221-34.

The role of pineal gland in breast cancer development.
Anisimov VN.

Department of Carcinogenesis and Oncogerontology, N.N. Petrov Research Institute of Oncology, Pesochny-2, 197758, St. Petersburg, Russia. aging@mail.ru

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.

Light during darkness, melatonin suppression and cancer progression.

Neuro Endocrinol Lett. 2002 Jul;23 Suppl 2:52-6.

Light during darkness, melatonin suppression and cancer progression.
Blask DE, Dauchy RT, Sauer LA, Krause JA, Brainard GC.

Laboratory of Experimental Neuroendocrinology/Oncology, Bassett Research Institute, Cooperstown, NY 13326, USA. david.blask@bassett.org

Over the past few years, we have shown that the surge of melatonin in the circulation during darkness represents a potent oncostatic signal to tissue-isolated rat hepatoma 7288CTC, which is an ER+ adenocarcinoma of the liver. This oncostatic effect occurs via a melatonin receptor-mediated suppression of tumor cAMP production that leads to a suppression of the tumor uptake of linoleic acid (LA), an essential fatty acid with substantial oncogenic properties. The ability of LA to promote cancer progression is accomplished by its intracellular metabolism to 13-hydroxyoctadecadienoic acid (13-HODE) which amplifies the activity of the epidermal growth factor receptor/mitogen-activated protein kinase pathway leading to cell proliferation. By blocking tumor LA uptake, melatonin effectively blocks the production of 13-HODE and thus, markedly attenuates tumor growth. A similar effect of melatonin is observed in tissue-isolated, ER+ MCF-7 human breast cancer xenografts and nitrosomethylurea (NMU)-induced rat mammary cancers. When male rats bearing tissue-isolated hepatomas are exposed either to constant bright light (300 lux) or dim light (0.25 lux) during the dark phase of a 12L:12D photoperiod, the latency to onset was significantly reduced while the growth of tumors was markedly increased over a 4 wk period as compared with control tumors in 12L:12D-exposed rats. In constant light- and dim light during darkness-exposed rats, melatonin levels were completely suppressed while tumor growth, LA uptake and 13-HODE production were markedly increased. Similar results were obtained in constant bright light-exposed female rats bearing tissue-isolated NMU-induced mammary cancers or MCF-7 human breast cancer xenografts. To date, these studies provide the most definitive experimental evidence that light exposure during darkness increases the risk of cancer progression via elimination of the nocturnal melatonin signal and its suppression of tumor LA uptake and metabolism to 13-HODE.

Light at Night, Shiftwork, and Breast Cancer Risk

Light at Night, Shiftwork, and Breast Cancer Risk

Correspondence to: Johnni Hansen, Ph.D., Danish Cancer Society, Institute of Cancer Epidemiology, Strandboulevarden 49, DK-2100 Copenhagen, Denmark (e-mail: johnni@cancer.dk).
Breast cancer is the most commonly diagnosed female noncutaneous cancer in the United States and in Europe. The etiology of breast cancer is primarily unknown, with an estimated one quarter of all breast cancers possibly due to heritable factors (1) and only a minor proportion possibly due to already established environmental risk factors, such as early age at menarche, older age at first pregnancy, and delayed menopause (2). Because the incidence of breast cancer in many countries is increasing, for unclear reasons, it is not surprising that society is demanding explanations for the increased incidence of the disease and that researchers are searching for new causes. One avenue of research has been the so-called “man-made endocrine disrupting chemicals,” such as 2-(chlorphenyl)-2-(4-chlorphenyl)-1,1,1-trichlorethan (DDT), polychlorinated biphenyls, or nonyl phenols (3). So far, however, the results from this research have been sparse in expanding our knowledge about risk factors for breast cancer.

In this issue of the Journal, two independent epidemiologic studies by Davis et al. (4) and Schernhammer et al. (5) have provided evidence about another potential risk factor, light at night. These studies (4,,5) support a hypothesis published about 10 years ago by the former group that light at night may be a potential risk factor of breast cancer (6,,7).

The scientific rationale behind this intriguing hypothesis is that exposure to visible light, including artificial light, suppresses the normal nocturnal production of melatonin by the pineal gland (6). Melatonin is a mammalian hormone involved in circadian rhythms and sleep and potentially in restraining tumor growth (8). The synthesis and release of melatonin occur in a dose–response-like manner that is stimulated by darkness and inhibited by light through photic information from the retina. Peak melatonin levels normally occur during sleep in the middle of the night (8). Several experimental studies have provided evidence of an association between melatonin levels and risk of cancer. For example, evidence from rodent studies found that pinealectomy increased tumor growth (9), that administration of melatonin inhibited the promotion of chemically induced mammary tumors (9,,10), and that constant light exposure had a growth-promoting effect on chemically induced tumors (11). Evidence in humans is less direct, although impaired pineal secretion of melatonin is associated with an increased release of estrogen by the ovaries (7,,8), and low serum melatonin concentrations have been reported in women with estrogen receptor-positive breast cancer (8).In vitro, physiologic concentrations of melatonin inhibited the growth of human breast cancer cells (12). Several mechanisms involved in the apparent protective effect of melatonin have been suggested; they include a direct antiproliferative effect (13), increased immune responses (8), scavenging of free radicals (8), and modulation of the expression of the tumor suppressor gene p53 (14).

The case–control study by Davis et al. (4) in this issue is based on in-person interviews with 814 breast cancer patients and 793 control subjects. The participation rate for both case patients and control subjects was relatively high, i.e., 78% and 75%, respectively. Graveyard shift work (defined as beginning work after 7:00 pm and leaving work before 9:00 am) was associated with a 60% increase in breast cancer risk (odds ratio = 1.6; 95% confidence interval = 1.0 to 2.5) and with a trend of increasing risk with increasing number of years of work or with more hours per week of graveyard shift work. Furthermore, Davis et al. found that independently of the shift-work status, women who frequently do not sleep during the period of the night when melatonin levels are typically at their highest have a 14% increase in breast cancer risk for each night per week. Finally, there was an indication of an increased risk among subjects with the brightest bedrooms, but there was no association with interrupted sleep accompanied by turning on a light. The strength of this study is the detailed collection of information on exposure, including sleep patterns, bedroom environments, and shift work.

The prospective cohort study by Schernhammer et al. (5) in this issue uses data from the Nurses` Health Study, in which 78 562 women in 1988 responded to a question regarding how many years they had worked rotating nightshifts, with at least three nights per month. This cohort was followed from 1988 through 1998, during which 2411 first primary breast cancers were diagnosed. Compared with those who had done no nightshift work at all, nurses who had performed nightshift work for between 1 and 29 years showed an 8% increase in relative risk of breast cancer, and nurses with at least 30 years of nightshift work showed a 36% increase in relative risk. The strength of this study is its prospective design and the large number of relatively homogeneous participants and long follow-up.

Although these two well-conducted studies have different approaches to defining exposure to light at night, neither is optimal. For example, both studies are prone to exposure misclassification, although the general effect of such misclassification would bias the risk estimates toward unity and, thus, would underestimate the true increased risk. However, both studies have adjusted their outcomes for known confounders, such as reproductive history, family history of breast cancer, use of oral contraceptives and hormone replacement therapy, social class, and alcohol consumption. Therefore, with different epidemiologic designs (each with its own strengths) and with results pointing in the same direction, the studies are complementary.

Evidence is accumulating for an association between exposure to light at night and breast cancer risk. Table 1⇔ provides an overview of three published studies (4,5,,15), including the two studies in this issue, where the hypothesis of work at night and breast cancer risk is evaluated, each study controlled for reproductive history. Positive associations between shiftwork and breast cancer risk were also observed in three smaller cohort studies (16–,18) conducted for purposes other than testing the melatonin hypothesis, but these studies did not adjust for reproductive history and other confounders for breast cancer. Finally, indirect support for the melatonin hypothesis comes from studies on blind women (19–,23) who are not sensitive to changes in light and, consequently, whose melatonin levels do not change. Studies show an approximately 20%–50% reduced risk of breast cancer among such women (19–,22), with a tendency toward an inverse dose–response relationship between the degree of blindness and breast cancer risk (23).

Although the possibility exists that work at night or exposure to light at night acts as a proxy for other yet unknown risk factors for breast cancer, and acknowledging that a publication bias may exist, apparently all of epidemiologic studies published so far (4,5,15–,18) on different indirect measures of light at night and breast cancer risk seem to relatively consistently point to an increased risk. From an occupational point of view, these recent results are alarming, regardless of the underlying biologic cause for the apparent increased risk of breast cancer among women who work at night. No occupational exposures with known or potential carcinogenicity are as common as work at night. Moreover, during the last few decades, society has increased the diversity of irregular work hours, including work at night, and amount of irregular work hours, including work at night. To obtain experience in more ergonomic shift scheduling in general, it is, therefore, important, parallel to initiating new epidemiologic studies, to investigate whether changing shift scheduling may influence melatonin levels. This investigation may be efficiently accomplished by measuring morning urinary 6-hydroxymelatoninsulfate levels as a biomarker of nocturnal melatonin secretion (24). A recent study on Danish hospital workers (25) shows that changing the timing of work at night can positively change biomarkers for cardiovascular disease.

In conclusion, there is an urgent need for further exploration of the relationship between exposure to light at night, shiftwork, including timing during the night, and cancers that may be influenced by melatonin.

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Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor.

J Neurosci. 2001 Aug 15;21(16):6405-12.

Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor.
Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Gerner E, Rollag MD.

Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. george.brainard@mail.tju.edu

The photopigment in the human eye that transduces light for circadian and neuroendocrine regulation, is unknown. The aim of this study was to establish an action spectrum for light-induced melatonin suppression that could help elucidate the ocular photoreceptor system for regulating the human pineal gland. Subjects (37 females, 35 males, mean age of 24.5 +/- 0.3 years) were healthy and had normal color vision. Full-field, monochromatic light exposures took place between 2:00 and 3:30 A.M. while subjects` pupils were dilated. Blood samples collected before and after light exposures were quantified for melatonin. Each subject was tested with at least seven different irradiances of one wavelength with a minimum of 1 week between each nighttime exposure. Nighttime melatonin suppression tests (n = 627) were completed with wavelengths from 420 to 600 nm. The data were fit to eight univariant, sigmoidal fluence-response curves (R(2) = 0.81-0.95). The action spectrum constructed from these data fit an opsin template (R(2) = 0.91), which identifies 446-477 nm as the most potent wavelength region providing circadian input for regulating melatonin secretion. The results suggest that, in humans, a single photopigment may be primarily responsible for melatonin suppression, and its peak absorbance appears to be distinct from that of rod and cone cell photopigments for vision. The data also suggest that this new photopigment is retinaldehyde based. These findings suggest that there is a novel opsin photopigment in the human eye that mediates circadian photoreception.

Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor.

J Neurosci. 2001 Aug 15;21(16):6405-12.

Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor.
Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Gerner E, Rollag MD.

Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. george.brainard@mail.tju.edu

The photopigment in the human eye that transduces light for circadian and neuroendocrine regulation, is unknown. The aim of this study was to establish an action spectrum for light-induced melatonin suppression that could help elucidate the ocular photoreceptor system for regulating the human pineal gland. Subjects (37 females, 35 males, mean age of 24.5 +/- 0.3 years) were healthy and had normal color vision. Full-field, monochromatic light exposures took place between 2:00 and 3:30 A.M. while subjects` pupils were dilated. Blood samples collected before and after light exposures were quantified for melatonin. Each subject was tested with at least seven different irradiances of one wavelength with a minimum of 1 week between each nighttime exposure. Nighttime melatonin suppression tests (n = 627) were completed with wavelengths from 420 to 600 nm. The data were fit to eight univariant, sigmoidal fluence-response curves (R(2) = 0.81-0.95). The action spectrum constructed from these data fit an opsin template (R(2) = 0.91), which identifies 446-477 nm as the most potent wavelength region providing circadian input for regulating melatonin secretion. The results suggest that, in humans, a single photopigment may be primarily responsible for melatonin suppression, and its peak absorbance appears to be distinct from that of rod and cone cell photopigments for vision. The data also suggest that this new photopigment is retinaldehyde based. These findings suggest that there is a novel opsin photopigment in the human eye that mediates circadian photoreception.

Photoperiodism in humans and other primates: evidence and implications.

J Biol Rhythms.
2001 Aug;16(4):348-64.

Photoperiodism in humans and other primates: evidence and implications.

Wehr TA.

Section on Biological Rhythms, National Institute of Mental Health, Bethesda, MD, USA.

Most of the anatomical and molecular substrates of the system that encodes changes in photoperiod in the duration of melatonin secretion, and the receptor molecules that read this signal, have been shown to be conserved in monkeys and humans, and the functions of this system appear to be intact from the level of the retina to the level of the melatonin-duration signal of change of season. While photoperiodic seasonal breeding has been shown to occur in monkeys, it remains unclear whether photoperiod and mediation of photoperiod`s effects by melatonin influence human reproduction. Epidemiological evidence suggests that inhibition of fertility by heat in men in summer contributes to seasonal variation in human reproduction at lower latitudes and that stimulation of fertility by lengthening of the photoperiod in spring contributes to the variation at higher latitudes. Parallels between the seasonality of human reproduction and seasonal affective disorder suggest that they may be governed by common biological processes. Historical and experimental evidence indicates that human responses to seasonal changes in the natural photoperiod may have been more robust prior to the Industrial Revolution and that subsequently they have been increasingly suppressed by alterations of the physical environment.

Melatonin and mammary pathological growth.

Front Neuroendocrinol. 2000 Apr;21(2):133-70.

Cos S, Sanchez-Barcelo EJ.

Department of Physiology and Pharmacology, University of Cantabria, Santander, 39011, Spain.

In this article we review the state of the art on the role of the pineal gland and melatonin in mammary cancer tumorigenesis in vivo as well as in vitro. The former hypothesis of a possible role of the pineal gland in mammary cancer development was based on the evidence that the pineal, via its main secretory product, melatonin, downregulates some of the pituitary and gonadal hormones which control mammary gland development and are also responsible for the growth of hormone-dependent mammary tumors. Furthermore, melatonin could act directly on tumoral cells, thereby influencing their proliferative rate. Other possible origins of melatonin`s antitumoral actions could be found in its antioxidant or immunoenhancing properties. The working hypotheses of most experiments were that the activation of the pineal gland, or the administration of melatonin, should give rise to antitumoral behavior; conversely, suppression of the pineal gland or melatonin deficits should stimulate mammary tumorigenesis. From in vivo studies on animal models of tumorigenesis, the general conclusion is that experimental manipulations activating the pineal gland, or the administration of melatonin, enlarge the latency and reduce the incidence and growth rate of chemically induced mammary tumors, while pinealectomy usually has the opposite effects. The direct actions of melatonin on mammary tumors have been suggested because of its ability to inhibit, at physiological doses (1 nM), the in vitro proliferation and invasiveness of MCF-7 human breast cancer cells. The fact that most studies have been performed on two models, chemically induced mammary adenocarcinoma in rats (in vivo studies) and the cell tumor line MCF-7 (in vitro studies), makes the generalization of the results somewhat difficult. However, the characteristics of these actions, comprising different aspects of tumor biology such as initiation, proliferation, and metastasis, as well as the doses (physiological range) at which the effect is accomplished, give special value to these findings. On the strength of these data, the small number of clinical studies focusing on the possible therapeutic value of melatonin on breast cancer is surprising. Copyright 2000 Academic Press.

Melatonin, experimental basis for a possible application in breast cancer prevention and treatment.

Histol Histopathol. 2000 Apr;15(2):637-47.

Cos S, Sanchez-Barcelo EJ.
Department of Physiology and Pharmacology, School of Medicine, University of Cantabria, Santander, Spain.

The role of the pineal as an oncostatic gland has been studied in animal models of tumorigenesis, especially on those concerning the mammary gland. The general conclusion is that experimental manipulations activating pineal gland, or the administration of melatonin, reduce the incidence and growth rate of chemically-induced murine mammary tumors, while pinealectomy or situations which implicate a reduction of melatonin production usually stimulate mammary carcinogenesis. The direct actions of melatonin on mammary tumors have been suggested because of its ability to inhibit, at physiological doses (1nM), the in vitro proliferation of MCF-7 human breast cancer cells. In this article we review the outstanding findings related to melatonin actions on mammary which, taken together, support a possible usefulness of this indoleamine in the prevention and treatment of mammary gland malignancy.

Reduced cancer incidence among the blind.

Comment in:

  • Epidemiology. 1998 Sep;9(5):481-3.
  • Epidemiology. 1999 Nov;10(6):785.

Reduced cancer incidence among the blind.
Feychting M, Osterlund B, Ahlbom A.

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Melatonin is a hormone primarily produced by the pineal gland at night and is suppressed by exposure to light. Experimental studies have indicated that melatonin may protect against cancer development. In the majority of totally blind people, melatonin is never suppressed by light exposure. The aim of this study was to test the hypothesis that blind people have a decreased cancer incidence, and that this effect is more pronounced in the totally blind than in the severely visually impaired. We identified a cohort of 1,567 totally blind and 13,292 severely visually impaired subjects and obtained information about cancer incidence from the Swedish Cancer Registry. We calculated standardized incidence ratios (SIRs) based on the number of person-years and incidence rates specific for national age, sex, and calendar year. Totally blind people had a lower incidence of all cancers combined [SIR = 0.69; 95% confidence interval (CI) = 0.59-0.82]. The risk reduction was observed in both men and women and was equally pronounced in hormone-dependent tumors as in other types of cancer. In the severely visually impaired, SIR was 0.95 (95% CI = 0.91-1.00). The findings support the hypothesis that blind people have a lower cancer incidence, although other explanations than the higher melatonin exposure must also be considered.

Photoperiodic Effects On Tumor Development And Immune Function

J Biol Rhythms. 1994 Winter;9(3-4):233-49.
Related Articles, Links

Photoperiodic effects on tumor development and immune function.

Nelson RJ, Blom JM.

Department of Psychology, Johns Hopkins University, Baltimore, Maryland 21218, USA.

Seasonal changes in adaptations associated with winter coping strategies have been frequently studied. Central among the suite of energy-saving, winter-coping strategies is the suspension of reproductive activities. The inhibition of reproduction by nontropical rodents is mediated by daylength changes. Although balanced annual energy budgets are critical, survival and subsequent reproductive success also require avoiding predators, illness, and early death. Because the stressors of winter could lead to suppressed immune function, we hypothesized that animals should have evolved survival strategies involving immunoenhancement. Short daylengths provide a predictive cue to individuals that could be used to enhance immune function in advance of stress-induced immunosuppression. In Experiment 1, adult female deer mice (Peromyscus maniculatus) were housed in either long (LD 16:8) or short (LD 8:16) days for 8 weeks, then injected with the chemical carcinogen 9,10-dimethyl-1,2-benzanthracene (DMBA) dissolved in dimethyl sulfoxide (DMSO) or with the DMSO vehicle alone. Animals were evaluated weekly for 8 weeks after injection. None of the animals treated with DMSO developed tumors in any of the experiments. Nearly 90% of the long-day deer mice injected with DMBA developed squamous cell carcinoma. None of the short-day deer mice injected with DMBA developed tumors. Small lesions developed at the site of injection; short-day females had less severe lesions and healed faster than long-day females. Immunoglobulin G (IgG) response to i.p. injection of sheep red blood cells (SRBC) did not differ photoperiodic conditions. The role of estrogens in the photoperiodic responses was evaluated in Experiment 2: Ovariectomized or sham-ovariectomized deer mice received estradiol benzoate replacement therapy or a control procedure in long daylengths for 8 weeks prior to injection of DMBA or DMSO, then were monitored for 8 additional weeks. Females treated with DMBA developed tumors at the same rate, regardless of estrogen manipulation. Estrogen did not affect healing rates. In Experiment 3, female deer mice were injected with a slurry of microspheres that either contained bromocriptine or were empty. Suppression of prolactin with bromocriptine resulted in a decrease of tumor incidence from 55.6% to 24% in long-day females 8 weeks after injection with DMBA. Healing rates were not affected by prolactin manipulations. Silastic capsules that were filled with either melatonin or cholesterol were implanted into long-day female deer mice in Experiment 4; 8 weeks later, females received an injection of either DMBA or DMSO, then were monitored for 8 weeks.(ABSTRACT TRUNCATED AT 400 WORDS)