Affiliations of authors: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (ESS, SEH); Department of Epidemiology, Harvard School of Public Health, Boston, MA (ESS, SEH); LBI-ACR VIEnna and ACR-ITR VIEnna, Vienna, Austria (ESS)
Correspondence to: Eva S. Schernhammer, MD, DrPH, Channing Laboratory, 181 Longwood Ave., Boston, MA 02115 (e-mail: eva.schernhammer{at}channing.harvard.edu).
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ABSTRACT |
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Results of previous studies [reviewed in (13)] suggest that night-shift work, a surrogate for exposure to light at night, is associated with an increased risk of breast cancer and, possibly, other cancers. On the basis of results of laboratory and animal experiments (14,15), light-induced suppression of melatonin secretion has been hypothesized as the major cause of this association; however, the only prospective study conducted to date found no evidence that 24-hour levels of melatonin are strongly associated with the risk of breast cancer (16).
We used a nested casecontrol design to conduct a prospective study of the association between melatonin levels in first morning urine and breast cancer risk in a large cohort of primarily premenopausal women enrolled in the Nurses' Health Study II (NHSII). The Nurses' Health Study II was established in the United States in 1989, when 116671 female registered nurses aged 2542 years were enrolled after completing a baseline questionnaire. Since then, all participants have received a follow-up questionnaire every 2 years (17). Of these women, 29613 agreed to participate in a blood and urine collection substudy from 1996 to 1999 (see footnote to Table 2). In brief, each woman provided two blood samples over the course of 1 month, during the luteal and follicular phases of their menstrual cycles, and a single urine sample to which no preservative was added; all samples were stored in liquid nitrogen freezers. Further details of sample collection, processing, and storage methods have been described elsewhere (18). Overall, characteristics of the substudy participants were very similar to those of the total cohort at time of sample collection (data not shown).
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After excluding nine women (two case patients and seven control subjects) with missing aMT6s levels and one control subject whose aMT6s level was an outlier (20) from the total casecontrol set, 147 case patients with invasive breast cancer and 291 matched control subjects were available for our analyses. In secondary analyses, we included in situ breast cancer case patients and the matched control subjects, for a total of 190 case patients and 376 control subjects. Ten women (four case patients and six control subjects) had aMT6s levels that were below the limit of detection for the assay (i.e., <0.8 ng/mL); we considered their aMT6s levels before normalization to creatinine levels to be 0.8 ng/mL.
We used conditional regression models to estimate the relative risks of breast cancer (reported as odds ratios [ORs] with 95% confidence intervals [CIs]) by quartiles of urinary 6-sulphatoxymelatonin (aMT6s) concentrations, which were defined on the basis of the values for all control subjects. All models were adjusted for the casecontrol matching factors as well as for known risk factors for breast cancer (see Table 2 footnote). In a prior substudy, 80 NHSII participants had provided three luteal urine samples over a 3-year period (18); aMT6s levels were measured in all three samples and were found to be well correlated (intraclass correlation = 0.72, 95% CI = 0.65 to 0.82). We used the aMT6s measures from these 80 women to correct the point and interval estimates in the current dataset for laboratory measurement error and random within-person variation (21). All P values were two-sided.
Most of the women's baseline characteristics did not differ by casecontrol status (Table 1). However, the mean urinary aMT6s concentration of the invasive breast cancer case patients was statistically significantly lower than that of the control subjects (10.8 ng aMT6s/mg creatinine versus 12.7 ng aMT6s/mg creatinine; difference = 1.9 ng aMT6s/mg creatinine [95% CI = 0.6 to 3.2 ng aMT6s/mg creatinine; P = .03]). We also observed a statistically significant inverse association between urinary aMT6s concentrations and invasive breast cancer risk (OR for highest versus lowest quartile of urinary aMT6s concentration = 0.59, 95% CI = 0.36 to 0.97; Ptrend = .06; Table 2), with little change in these estimates after additional adjustment for breast cancer risk factors or for current smoking status, number of nights worked during the 2 weeks preceding urine collection, and lifetime history of night work. The inverse association between urinary aMT6s concentration and the risk of breast cancer was not statistically significant when we included case patients who were diagnosed with in situ breast cancer and the matched control subjects in the analysis (OR for highest versus lowest quartile of urinary aMT6s concentration = 0.70, 95% CI = 0.47 to 1.06).
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On the basis of results from a previous study that suggested that nocturnal plasma melatonin level is inversely correlated with tumor estrogen receptor (ER) concentration (22), we conducted an additional analysis among all women with invasive breast cancer stratified by tumor ER status (ER-positive versus ER-negative), and found that the association between urinary aMT6s levels and breast cancer risk among women with ER-positive tumors (OR for highest versus lowest quartile of urinary aMT6s concentration = 0.63, 95% CI = 0.32 to 1.24) was similar to that for all invasive cancers combined.
The association between urinary aMT6s level and breast cancer risk was largely unchanged after we excluded case patients who were diagnosed with invasive breast cancer within 2 years after their urine collection (OR for highest versus lowest quartile of urinary aMT6s concentration = 0.53, 95% CI = 0.29 to 0.97, Ptrend = .07) and after we excluded women who, at urine collection, reported that they were taking antidepressant medication, which can alter aMT6s secretion (23). For most of the women in this study, we had previously measured a number of plasma sex hormones (see Table 2 footnote); further adjustment for these hormones did not substantially change our results.
Finally, after correcting for laboratory measurement error and within-person variability, the odds ratio for highest versus lowest quartile of urinary aMT6s concentration decreased from 0.76 (95% CI = 0.58 to 1.01) to 0.60 (95% CI =0.35 to 1.02) for each 1-unit increase in log-transformed aMT6s concentrations, suggesting a modest underestimation of the true association because of measurement error.
In this nested casecontrol study, we observed 50 cases of breast cancer among the 25% of women (n = 7403) with the lowest aMT6s levels over the 4-year follow-up, compared with 23 cases of breast cancer in the 25% of women (n = 7403) with the highest aMT6s levels. Most previous studies of the association between circulating melatonin levels and breast cancer risk in humans are limited because melatonin levels were measured after the subjects were diagnosed with breast cancer (10,12,22, 2432). The only prospective study (16) found no association between melatonin levels and breast cancer risk. However, the authors of that study measured melatonin levels in pooled urine samples that had been collected over 24 hours, a measure that cannot detect potential differences between subjects in the nocturnal duration or the peak of melatonin secretion, which may be important for assessing an association between melatonin levels and breast cancer risk (33). The authors of that study also did not take into account the potential influence of alcohol consumption, night-shift work, or time of year (34)all of which are associated with melatonin productionon these associations. We were able to consider all these variables in our analyses. Excluding cases diagnosed within the first 2 years after urine collection did not alter our findings. However, with only 4 years of follow-up in our study, our ability to assess whether urinary aMT6s is a useful biomarker for breast cancer risk was limited, and larger studies with longer follow-up are needed to address this question more carefully. Another potential limitation of our study is that we did not have information on vitamin D levels in our study subjects, another possible breast cancer risk factor (35,36); it is conceivable that women whose exposure to sunlight is limited because they work at night have particularly low levels of vitamin D. However, our results remained essentially unchanged when we excluded night-shift workersthe group of women who would have lowest vitamin D levels if our theory was correctfrom the analysis. Moreover, given that the association between urinary aMT6s levels and breast cancer risk was essentially unchanged when we excluded women who had a history of night-shift work, it is unlikely that our findings are merely a reflection of a previously described association between night-shift work and breast cancer risk (37).
In summary, our findings indicatethat melatonin secretion, as assessed by aMT6s levels in first morning urine, may play an important role in breast cancer development. Further studies are needed to confirm our findings; these studies should address how melatonin levels measured in 24-hour urine samples differ from those measured in first morning urine. Finally, whether timing of sleepand thus timing of peak melatonin productionmatters in breast tumor development needs to be evaluated, especially if optimal sensitivity of the melatonin receptor RZR occurs at night (38).
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NOTES |
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REFERENCES |
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---|
(1) Czeisler CA, Klerman EB. Circadian and sleep-dependent regulation of hormone release in humans. Recent Prog Horm Res 1999;54:97130.[Medline]
(2) Czeisler CA, Duffy JF, Shanahan TL, Brown EN, Mitchell JF, Rimmer DW, et al. Stability, precision, and near-24-hour period of the human circadian pacemaker. Science 1999;284:217781.
(3) Arendt J. Melatonin and the pineal gland: influence on mammalian seasonal and circadian physiology. Rev Reprod 1998;3:1322.
(4) Zeitzer JM, Dijk DJ, Kronauer R, Brown EN, Czeisler C. Sensitivity of the human circadian pacemaker to nocturnal light: melatonin phase resetting and suppression. J Physiol 2000;526:695702.
(5) Leibenluft E, Feldman-Naim S, Turner EH, Schwartz PJ, Wehr TA. Salivary and plasma measures of dim light melatonin onset (DLMO) in patients with rapid cycling bipolar disorder. Biol Psychiatry 1996;40:7315.[CrossRef][ISI][Medline]
(6) Nowak R, McMillen IC, Redman J, Short RV. The correlation between serum and salivary melatonin concentrations and urinary 6-hydroxymelatonin sulphate excretion rates: two non-invasive techniques for monitoring human circadian rhythmicity. Clin Endocrinol 1987;27:44552.[ISI][Medline]
(7) Wetterberg L. Melatonin in humans physiological and clinical studies. J Neural Transm Suppl 1978;13:289310.[Medline]
(8) Lang U, Kornemark M, Aubert ML, Paunier L, Sizonenko PC. Radioimmunological determination of urinary melatonin in humans: correlation with plasma levels and typical 24-hour rhythmicity. J Clin Endocrinol Metab 1981;53:64550.[Abstract]
(9) Arendt J, Bojkowski C, Franey C, Wright J, Marks V. Immunoassay of 6-hydroxymelatonin sulfate in human plasma and urine: abolition of the urinary 24-hour rhythm with atenolol. J Clin Endocrinol Metab 1985;60:116673.[Abstract]
(10) Cook MR, Graham C, Kavet R, Stevens RG, Davis S, Kheifets L. Morning urinary assessment of nocturnal melatonin secretion in older women. J Pineal Res 2000;28:417.[CrossRef][ISI][Medline]
(11) Baskett JJ, Cockrem JF, Antunovich TA. Sulphatoxymelatonin excretion in older people: relationship to plasma melatonin and renal function. J Pineal Res 1998;24:5861.[ISI][Medline]
(12) Graham C, Cook MR, Kavet R, Sastre A, Smith DK. Prediction of nocturnal plasma melatonin from morning urinary measures. J Pineal Res 1998;24:2308.[ISI][Medline]
(13) Schernhammer ES, Hankinson SE. Light at night: a novel risk factor for cancer in shift workers? Clin Occup Environ Med 2003;3:26378.[CrossRef]
(14) Brzezinski A. Melatonin in humans. N Engl J Med 1997;336:18695.
(15) Vijayalaxmi, TC, Reiter RJ, Herman TS. Melatonin: from basic research to cancer treatment clinics. J Clin Oncol 2002;20:2575601.
(16) Travis RC, Allen DS, Fentiman IS, Key TJ. Melatonin and breast cancer: a prospective study. J Natl Cancer Inst 2004;96:47582.
(17) Rockhill B, Willett WC, Hunter DJ, Manson JE, Hankinson SE, Spiegelman D, et al. Physical activity and breast cancer risk in a cohort of young women. J Natl Cancer Inst 1998;90:115560.
(18) Schernhammer ES, Rosner B, Willett WC, Laden F, Colditz GA, Hankinson SE. Epidemiology of urinary melatonin in women and its relation to other hormones and night work. Cancer Epidemiol Biomarkers Prev 2004;13:93643.
(19) Adebamowo CA, Cho E, Sampson L, Katan MB, Spiegelman D, Willett WC, et al. Dietary flavonols and flavonol-rich foods intake and the risk of breast cancer. Int J Cancer 2005;114:62833.[CrossRef][ISI][Medline]
(20) Rosner B. Percentage points for a generalized ESD many-outlier procedure. Technometrics 1983;25:16572.[ISI]
(21) Rosner B, Spiegelman D, Willett WC. Correction of logistic regression relative risk estimates and confidence intervals for random within-person measurement error. Am J Epidemiol 1992;136:140013.[Abstract]
(22) Tamarkin L, Danforth D, Lichter A, DeMoss E, Cohen M, Chabner B, et al. Decreased nocturnal plasma melatonin peak in patients with estrogen receptor positive breast cancer. Science 1982;216:10035.[ISI][Medline]
(23) Murphy DL, Garrick NA, Tamarkin L, Taylor PL, Markey SP. Effects of antidepressants and other psychotropic drugs on melatonin release and pineal gland function. J Neural Transm Suppl 1986;21:291309.[Medline]
(24) Bartsch C, Bartsch H, Jain AK, Laumas KR, Wetterberg L. Urinary melatonin levels in human breast cancer patients. J Neural Transm 1981;52:28194.[CrossRef][ISI]
(25) Danforth DN, Tamarkin L, Mulvihill JJ, Bagley CS, Lippman ME. Plasma melatonin and the hormone-dependency of human breast cancer. J Clin Oncol 1985;3:9418.
(26) Lissoni P, Bastone A, Sala R, Mauri R, Rovelli F, Viviani S, et al. The clinical significance of melatonin serum determination in oncological patients and its correlations with GH and PRL blood levels. Eur J Cancer Clin Oncol 1987;23:94957.[CrossRef][ISI][Medline]
(27) Bartsch C, Bartsch H, Fuchs U, Lippert TH, Bellmann O, Gupta D. Stage-dependent depression of melatonin in patients with primary breast cancer. Correlation with prolactin, thyroid stimulating hormone, and steroid receptors. Cancer 1989;64:42633.[ISI][Medline]
(28) Lissoni P, Crispino S, Barni S, Sormani A, Brivio F, Pelizzoni F, et al. Pineal gland and tumor cell kinetics: serum levels of melatonin in relation to Ki-67 labeling rate in breast cancer. Oncology 1990;47:2757.[ISI][Medline]
(29) Skene DJ, Bojkowski CJ, Currie JE, Wright J, Boulter PS, Arendt J. 6-sulphatoxymelatonin production in breast cancer patients. J Pineal Res 1990;8:26976.[ISI][Medline]
(30) Falkson G, Falkson HC, Steyn ME, Rapoport BL, Meyer BJ. Plasma melatonin in patients with breast cancer. Oncology 1990;47:4015.[ISI][Medline]
(31) Bartsch C, Bartsch H, Bellmann O, Lippert TH. Depression of serum melatonin in patients with primary breast cancer is not due to an increased peripheral metabolism. Cancer 1991;67:16814.[ISI][Medline]
(32) Bartsch C, Bartsch H, Karenovics A, Franz H, Peiker G, Mecke D. Nocturnal urinary 6-sulphatoxymelatonin excretion is decreased in primary breast cancer patients compared to age-matched controls and shows negative correlation with tumor-size. J Pineal Res 1997;23:538.[ISI][Medline]
(33) Hrushesky WJ, Blask DE. Re: Melatonin and breast cancer: a prospective study. J Natl Cancer Inst 2004;96:8889.
(34) Beck-Friis J, von Rosen D, Kjellman BF, Ljunggren JG, Wetterberg L. Melatonin in relation to body measures, sex, age, season and the use of drugs in patients with major affective disorders and healthy subjects. Psychoneuroendocrinology 1984;9:26177.[CrossRef][ISI][Medline]
(35) Zhang SM. Role of vitamins in the risk, prevention, and treatment of breast cancer. Curr Opin Obstet Gynecol 2004;16:1925.[ISI][Medline]
(36) Welsh J. Vitamin D and breast cancer: insights from animal models. Am J Clin Nutr 2004;80:1721S4S.
(37) Schernhammer ES, Laden F, Speizer FE, Willett WC, Hunter DJ, Kawachi I, et al. Rotating night shifts and risk of breast cancer in women participating in the Nurses' Health Study. J Natl Cancer Inst 2001;93:15638.
(38) Girgert R, Bartsch C, Hill SM, Kreienberg R, Hanf V. Tracking the elusive antiestrogenic effect of melatonin: a new methodological approach. Neuro Endocrinol Lett 2003;24:4404.[Medline]
(39) Hankinson SE, Willett WC, Manson JE, Colditz GA, Hunter DJ, Spiegelman D, et al. Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 1998;90:12929.
Manuscript received December 3, 2004; revised May 9, 2005; accepted May 10, 2005.
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