`
`Commentary/Hypothesis
`
`Does ‘‘Clock’’ Matter in Prostate Cancer?
`
`Yong Zhu,1 Tongzhang Zheng,1 Richard G. Stevens,2 Yawei Zhang,1 and Peter Boyle3
`
`1Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut;
`2University of Connecticut Health Center, Farmington, Connecticut; and 3IARC, Lyon Cedex, France
`
`Abstract
`
`The ancient adaptation of a 24-hour circadian clock has
`profound effect on our daily biochemical, physiologic, and
`behavioral processes, including the monitoring of sex hor-
`mone levels. Although the disruption of the circadian cycle
`has been implicated in the etiology of hormone-related female
`breast cancer, few studies have been undertaken to determine
`if a link exists in the development of the most common cancer
`type among men whose etiology remains largely unknown:
`hormone-related prostate cancer. Here, we hypothesize that
`both altered-lighted environments and genetic variations in
`
`genes responsible for maintaining circadian rhythms may
`result in deregulation of clock-associated biological process-
`es, such as androgen expression, and consequently influence
`an individual’s risk of prostate cancer. There is also a potential
`for the interaction of genetic variants and exposures, such as
`evening shift work. Confirmation of this hypothesis will
`add to our understanding of the role of the circadian clock
`in prostate tumorigenesis and further facilitate the develop-
`ment of novel risk and prognostic biomarkers for prostate
`(Cancer Epidemiol Biomarkers Prev 2006;15(1):3 – 5)
`cancer.
`
`Introduction
`
`Prostate cancer is the most common and the second most
`fatal cancer among men in the industrialized world. Despite
`tremendous efforts to improve our understanding of this
`cancer, its etiology remains largely unknown. To date, the only
`well-established risk factors for prostate cancer are older age,
`family history of the disease, and race. Recent studies of
`another hormone-related cancer, breast cancer, have supported
`the hypothesis that circadian disruption may be a novel risk
`factor and that genetic determinants for circadian rhythms
`may play a role in breast tumorigenesis (1, 2). It is from these
`encouraging findings that we postulate that both circadian
`disturbance and genetic variations that alter functions of
`circadian genes are involved in hormone-related prostate
`tumorigenesis among men.
`
`Clock-Cancer Connection: Epidemiologic Evidence
`
`One fundamental component of our biological world is a
`universal 24-hour oscillation in biochemical, physiologic,
`and behavioral processes, which occurs in almost all living
`organisms due to an ancient adaptation to the rotation of the
`earth. Disruptions of
`these critical rhythms may have a
`profound influence on our health and might be involved in
`tumorigenesis (3).
`The clock-cancer connection has been investigated in studies
`of pilots, flight attendants, and shift workers who are more
`likely to have disrupted circadian cycles due to abnormal work
`hours. Observations from a Nordic pilots cohort showed that
`the relative risk of prostate cancer increased as the number of
`flight hours in long distance aircraft increased (4). A similar
`cohort of men working for Air Canada showed a significantly
`
`Received 8/15/05; revised 10/7/05; accepted 11/15/05.
`Grant support: NIH grants CA110937, CA62986, ES11659, and CA108369.
`The costs of publication of this article were defrayed in part by the payment of page charges.
`This article must therefore be hereby marked advertisement in accordance with 18 U.S.C.
`Section 1734 solely to indicate this fact.
`Requests for reprints: Yong Zhu, Department of Epidemiology and Public Health, Yale
`University School of Medicine, New Haven, CT 06520. Phone: 203-785-4844; Fax: 203-737-6023.
`E-mail: yong.zhu@yale.edu
`Copyright D 2006 American Association for Cancer Research.
`doi:10.1158/1055-9965.EPI-05-0631
`
`increased incidence rate of prostate cancer when compared
`with the respective Canadian population rates (5). These
`increased rates of prostate cancer may be due to circadian
`hormonal disturbances associated with long distance flights
`although confounding by other factors cannot be ruled out.
`Similarly, an increased risk of breast cancer among female
`flight attendants has also been observed (6). In addition, recent
`studies in female shift workers who work predominantly
`at night have reported an elevated risk for breast cancer
`(reviewed in ref. 7). This hypothesis was based on a light-at-
`night suppression of melatonin (8). Analogously, melatonin
`has been reported to be lower in men with prostate cancer than
`those without (9) and melatonin has been shown in vitro to
`modulate prostate cancer cell growth via androgen receptor
`interactions (10). The clock-cancer connection has gained some
`very limited but consistent support from previous studies.
`Other findings that may support a connection between
`circadian rhythms and cancer risk come from studies of the
`blind, who have a reduced or abolished sensitivity to
`environmental light exposures (11). In studies of totally blind
`men, prostate cancer risk was reduced (12, 13) although this
`reduction was not significant. A reduced risk of breast cancer
`has also been reported among blind women (13-15).
`These observations have suggested a role for circadian
`rhythms in the etiology of both prostate and breast cancers
`as previously proposed (16), which implies some common
`etiologic features shared by these two hormone-related cancer
`types. However,
`little is known about possible molecular
`mechanisms underlying this clock-cancer connection.
`
`Circadian Genes and Their Roles in Tumorigenesis
`
`Emerging areas of interest for circadian and cancer research are
`the roles of several newly identified clock genes in the master
`circadian pacemaker of the suprachiasmatic nucleus and in
`the peripheral cells and tissues, and how this clock apparatus
`controls the expression of a wide variety of genes. To date, there
`have been nine core circadian genes identified: Clock, casein
`kinase Ie (CKIe), cryptochrome 1 (Cry1), chryptochrome 2 (Cry2),
`Period1 (Per1), Period2 (Per2), and Period3 (Per3), Bmal1, and
`NPAS2. A model of transcription-translation feedback loops
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`Cancer Epidemiol Biomarkers Prev 2006;15(1). January 2006
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`4
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`Does ‘‘Clock’’ Matter in Prostate Cancer?
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`of these circadian genes has been proposed to explain the
`molecular clockwork (17) in which cell functions are regulated
`through the expression of clock-controlled genes. It has been
`estimated that 2% to 10% of all mammalian genes are clock-
`controlled genes,
`indicating an extensive circadian gene
`regulation (18).
`Recent findings suggest that circadian genes may function as
`tumor suppressors at the systemic, cellular, and molecular
`levels due to their involvement in cell proliferation, apoptosis,
`cell cycle control, and DNA damage response (reviewed in ref.
`3). In humans, the rhythmic expression of several cyclins and
`tumor suppressor p53 is regulated by the circadian clock (19). It
`has also been shown that the core circadian regulator, casein
`kinase I, functions in promoting cell proliferation and tumor-
`igenesis (20). A recent study showed that g radiation – induced
`apoptosis is circadian time dependent and disruption of the
`Per2 gene stops the response of all core circadian genes to g
`radiation (21). Moreover, disruption of circadian rhythms in
`mice is associated with accelerated growth of malignant tumors,
`suggesting that the host circadian clock may play an important
`role in endogenous control of tumor progression (22).
`
`Polymorphisms in Circadian Genes: Phenotypic Effects
`
`Several molecular epidemiologic studies have examined genetic
`polymorphisms in clock-related genes and corresponding
`phenotypes, such as morning/evening preference and depres-
`sive symptoms. A single nucleotide polymorphism located in
`the 3V flanking region of the human clock gene was reported
`to be a predictor of diurnal preference in a population-based
`randomly selected subjects (23). In addition, associations of Per3
`polymorphisms with delayed sleep phase syndrome or diurnal
`preference have recently been reported (24, 25). In the first study
`of a circadian gene variant and risk of cancer, we reported that
`the variant Per3 genotype was significantly associated with an
`increased risk of breast cancer among premenopausal women
`(1). Findings from this study and other association studies with
`other circadian gene variants require much more work to be
`confirmed. If associations of circadian gene variants with cancer
`risk exist, then an obvious question becomes how these variants
`might interact with exposures such as shift work to modify their
`effects on risk. For example, a variant which predisposes to
`morning preference may be particularly detrimental for night
`workers.
`
`Possible Mechanisms: Clock-Controlled Androgen
`Expression?
`
`The prostate is an androgen-dependent organ because andro-
`gens are essential for its normal growth and maintenance.
`Androgen may act as a carcinogen by increasing cellular
`proliferation and thereby increase the chance of random
`DNA copy errors. Evidence from animal studies has shown
`that large amounts of androgens given to rodents can induce
`prostate cancer (26). A human study also reported that long-
`term exposure to high levels of androgens is associated with
`prostate cancer risk (27). Levels of testosterone, a principle
`circulating androgen, have further been shown to play a
`pivotal role in the differentiation and maintenance of selected
`prostate cancer cells lines both in vitro and in vivo (28).
`The effect of circadian rhythms on the expression of
`androgens has been previously documented in animals (29).
`In men, a circadian pattern, with regard to the levels of serum
`total testosterone, has also been observed and this circadian
`rhythm becomes blunted with normal aging (30). Circadian
`rhythms in the plasma levels of cortisol, dehydroepiandroster-
`one, y4-androstenedione, testosterone, and dihydrotestoster-
`one have also been detected in healthy young men (31). These
`observations suggest that expression of these androgens might
`be controlled by circadian rhythms. Moreover, circadian
`genes are directly involved in the regulation of tumor-related
`genes in prostate tumorigenesis. For example, the expression
`of cyclin D1 is deregulated in Per2 mutant mice (32). Cyclin D1
`activates the cyclin-dependent kinase 6 that may bind to the
`androgen receptor and stimulate its transcriptional activity in
`the presence of dihydrotestosterone (33).
`The above findings suggest that androgens might play a role
`in prostate cancer development. Given the possible effect of the
`circadian rhythm on androgen expression, we postulate that
`circadian disruptions, caused by both genetic and environmen-
`tal factors, may affect androgen expression patterns and
`consequently contribute to prostate cancer development, off-
`ering a potential mechanism for prostate tumorigenesis (Fig. 1).
`
`Hypothesis
`
`We hypothesize that circadian disruption may explain some
`etiology of prostate cancer and may provide a novel panel
`of biomarkers to determine an individual’s associated risk.
`
`Figure 1. Proposed role of the circadian clock in prostate
`tumorigenesis. The circadian rhythms can be affected by either
`genetic variants in circadian genes or altered light exposure.
`Consequently, androgen expression and biological pathways
`regulated by circadian rhythms may contribute to prostate
`cancer development and progression. In addition, circadian
`genes are directly involved in the regulation of tumor-related
`genes (such as cyclin D1) in prostate tumorigenesis.
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`Cancer Epidemiol Biomarkers Prev 2006;15(1). January 2006
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`Cancer Epidemiology, Biomarkers & Prevention
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`5
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`Specifically, increased exposure to light at night will disrupt
`circadian rhythms and consequently elevate the risk of
`prostate cancer. In addition, genetic and epigenetic variations
`in circadian genes may result in deregulation of circadian
`rhythms and other biological processes regulated by these
`genes; we propose that genetic variations and methylation
`changes altering the expression and functionality of circadian
`genes will be potential biomarkers associated with an
`individual’s risk of prostate cancer.
`
`Testing the Hypothesis
`
`From an epidemiologic perspective, a well-designed, popula-
`tion-based case-control study would provide evidence for the
`role of circadian disruption in prostate cancer. In this type
`of study, the questionnaire for assessing environmental light
`exposures and sleeping patterns must be carefully designed to
`ensure revealing results. Additional studies involving noctur-
`nal occupational groups, such as shift workers, would also test
`the hypothesis in prostate cancer.
`Genetic and epigenetic analyses of the circadian genes
`will further illustrate the role of circadian genes in prostate
`tumorigenesis. Three approaches could be applied in this
`regard: (a) candidate genetic variation approach, to examine
`associations between genotypes and haplotypes of predicted
`functional single nucleotide polymorphisms in the circadian
`genes and prostate cancer risk; (b) whole gene approach, to
`investigate associations between haplotypes estimated from
`haplotype-tagging single nucleotide polymorphisms in the
`circadian genes and prostate cancer risk; and (c) epigenetic
`approach, to explore changes of methylation status in CpG
`islands of the circadian genes as biomarkers for prostate cancer.
`Analysis on the joint-effect of circadian biomarkers and
`environmental factors would also test the hypothesis that
`increased exposure to light at night may elevate the risk of
`prostate cancer for individuals with the putative high-risk
`genotypes and haplotypes of circadian genes. Furthermore,
`determining possible associations between shift work and
`level of androgens, such as testosterone, may help to illustrate
`potential effects of aberrant
`light exposures on androgen
`expressions and provide a likely molecular mechanism should
`an increased risk be observed between shift work and prostate
`cancer.
`
`Conclusions
`
`We propose that some prostate cancer cases could be
`explained by light-induced circadian disruptions and/or
`genetic/epigenetic variations in circadian genes and/or gene-
`environment interactions between these two factors. We also
`propose that the clock-regulated androgen expressions might
`be one potential mechanism involved in prostate tumorigen-
`esis. These hypotheses are testable in a molecular epidemio-
`logic study and could lead to the development of novel risk
`and prognostic biomarkers.
`
`Acknowledgments
`We thank Carly Guss (Yale University, New Haven, CT) and Derek
`Leaderer (Colby College, Waterville, ME) for their careful reading and
`comments on the manuscript.
`
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