Breast Cancer Research and Treatment

, Volume 127, Issue 2, pp 531–540 | Cite as

The role of polymorphisms in circadian pathway genes in breast tumorigenesis

  • Hongji Dai
  • Lina Zhang
  • Mingli Cao
  • Fengju Song
  • Hong Zheng
  • Xiaoling Zhu
  • Qingyi Wei
  • Wei Zhang
  • Kexin Chen


Disruption of the circadian rhythm or biological clock, which is regulated by a number of clock genes, including circadian locomotor output cycles kaput (CLOCK), period genes (PERs), and cryptochrome genes (CRYs), is a risk factor for breast cancer. We hypothesized that genetic variation in these clock genes may influence breast cancer risk. To test this hypothesis, we designed a hospital-based study that included 1,538 breast cancer patients and 1,605 healthy controls. We genotyped subjects for five single nucleotide polymorphisms (SNPs) and a length variant of the circadian clock genes and evaluated their associations with breast cancer risk. These polymorphisms were determined by TaqMan allelic discrimination assays and the polymerase chain reaction-restriction fragment length polymorphism method. Univariate logistic regression analysis showed that polymorphisms of the CLOCK and CRY1 genes were associated with breast cancer risk. We found that carriers of the CLOCK CT and combined CT+TT genotypes had a significantly higher risk of breast cancer than carriers of the CC genotype (aOR = 1.35, 95% CI = 1.12-1.63 and aOR = 1.30, 95% CI = 1.09–1.56, respectively). Carriers of the CRY1 GT genotype had a decreased risk of breast cancer (aOR = 0.84, 95% CI = 0.71–0.99). We also observed a lower risk of breast cancer in carriers of the CRY2 CC genotype who were ER-positive than in those who were ER-negative (OR = 0.15, 95% CI = 0.04–0.67). When stratified by the CLOCK genotype, patients with the CLOCK CT/CRY2 CC genotypes had significantly lower cancer risk than those with the GG genotype (aOR = 0.36, 95% CI = 0.14–0.95). Individuals carrying both the CLOCK CC and PER2 AA genotypes had an increased cancer risk (aOR = 2.28, 95% CI = 1.22–4.26). Our study suggests that genetic variants of the circadian rhythm regulatory pathway genes contribute to the differential risk of developing breast cancer in Chinese populations.


Circadian rhythm Clock gene Genetic polymorphism Breast cancer 



Circadian locomotor output cycles kaput


Brain and muscle ARNT-like1


Single nucleotide polymorphisms


Restriction fragment length polymorphism


Polymerase chain reaction


Adjusted odds ratios


Confidence intervals

Supplementary material

10549_2010_1231_MOESM1_ESM.docx (513 kb)
Supplementary material 1 (DOCX 513 kb)


  1. 1.
    Parkin DM, Bray F, Ferlay J et al (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108. doi:10.3322/canjclin.55.2.74 PubMedCrossRefGoogle Scholar
  2. 2.
    Linos E, Spanos D, Rosner BA et al (2008) Effects of reproductive and demographic changes on breast cancer incidence in China: a modeling analysis. J Natl Cancer Inst 100:1352–1360. doi:10.1093/jnci/djn305 PubMedCrossRefGoogle Scholar
  3. 3.
    Burch JB, Walling M, Rush A et al (2007) Melatonin and estrogen in breast cyst fluids. Breast Cancer Res Treat 103:331–341. doi:10.1007/s10549-006-9372-z PubMedCrossRefGoogle Scholar
  4. 4.
    Hankinson SE, Eliassen AH (2007) Endogenous estrogen, testosterone and progesterone levels in relation to breast cancer risk. J Steroid Biochem Mol Biol 106:24–30. doi:10.1016/j.jsbmb.2007.05.012 PubMedCrossRefGoogle Scholar
  5. 5.
    Yu H, Shu XO, Li BD et al (2003) Joint effect of insulin-like growth factors and sex steroids on breast cancer risk. Cancer Epidemiol Biomarkers Prev 12:1067–1073PubMedGoogle Scholar
  6. 6.
    Ravdin PM, Cronin KA, Howlader N et al (2007) The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med 356:1670–1674. doi:10.1056/NEJMsr070105 PubMedCrossRefGoogle Scholar
  7. 7.
    Kubo T, Ozasa K, Mikami K et al (2006) Prospective cohort study of the risk of prostate cancer among rotating-shift workers: findings from the Japan collaborative cohort study. Am J Epidemiol 164:549–555. doi:10.1093/aje/kwj232 PubMedCrossRefGoogle Scholar
  8. 8.
    Viswanathan AN, Hankinson SE, Schernhammer ES (2007) Night shift work and the risk of endometrial cancer. Cancer Res 67:10618–10622. doi:10.1158/0008-5472.CAN-07-2485 PubMedCrossRefGoogle Scholar
  9. 9.
    Schernhammer ES, Laden F, Speizer FE et al (2003) Night-shift work and risk of colorectal cancer in the nurses’ health study. J Natl Cancer Inst 95:825–828PubMedCrossRefGoogle Scholar
  10. 10.
    Schernhammer ES, Kroenke CH, Laden F et al (2006) Night work and risk of breast cancer. Epidemiology 17:108–111. doi:10.1097/01.ede.0000190539.03500.c1 PubMedCrossRefGoogle Scholar
  11. 11.
    Maemura K, Takeda N, Nagai R (2007) Circadian rhythms in the CNS and peripheral clock disorders: role of the biological clock in cardiovascular diseases. J Pharmacol Sci 103:134–138. doi:10.1254/jphs.FMJ06003X2 PubMedCrossRefGoogle Scholar
  12. 12.
    Knutsson A (2003) Health disorders of shift workers. Occup Med (Lond) 53:103–108. doi:10.1093/occmed/kqg048 CrossRefGoogle Scholar
  13. 13.
    Costa G (2003) Shift work and occupational medicine: an overview. Occup Med (Lond) 53:83–88. doi:10.1093/occmed/kqg045 CrossRefGoogle Scholar
  14. 14.
    Stevens RG (1987) Electric power use and breast cancer: a hypothesis. Am J Epidemiol 125:556–561PubMedGoogle Scholar
  15. 15.
    Albrecht U (2002) Invited review: regulation of mammalian circadian clock genes. J Appl Physiol 92:1348–1355. doi:10.1152/japplphysiol.00759.2001 PubMedGoogle Scholar
  16. 16.
    Ueda HR, Hayashi S, Chen W et al (2005) System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nat Genet 37:187–192. doi:10.1038/ng1504 PubMedCrossRefGoogle Scholar
  17. 17.
    Delaunay F, Laudet V (2002) Circadian clock and microarrays: mammalian genome gets rhythm. Trends Genet 18:595–597. doi:10.1016/S0168-9525(02)02794-4 PubMedCrossRefGoogle Scholar
  18. 18.
    Canaple L, Kakizawa T, Laudet V (2003) The days and nights of cancer cells. Cancer Res 63:7545–7552PubMedGoogle Scholar
  19. 19.
    Zhu Y, Brown HN, Zhang Y et al (2005) Period3 structural variation: a circadian biomarker associated with breast cancer in young women. Cancer Epidemiol Biomarkers Prev 14:268–270PubMedGoogle Scholar
  20. 20.
    Hoffman AE, Yi CH, Zheng T et al (2010) CLOCK in breast tumorigenesis: genetic, epigenetic, and transcriptional profiling analyses. Cancer Res 70:1459–1468. doi:10.1158/0008-5472.CAN-09-3798 PubMedCrossRefGoogle Scholar
  21. 21.
    Zhu Y, Stevens RG, Leaderer D et al (2008) Non-synonymous polymorphisms in the circadian gene NPAS2 and breast cancer risk. Breast Cancer Res Treat 107:421–425. doi:10.1007/s10549-007-9565-0 PubMedCrossRefGoogle Scholar
  22. 22.
    Zhu Y, Leaderer D, Guss C et al (2007) Ala394Thr polymorphism in the clock gene NPAS2: a circadian modifier for the risk of non-Hodgkin’s lymphoma. Int J Cancer 120:432–435. doi:10.1002/ijc.22321 PubMedCrossRefGoogle Scholar
  23. 23.
    Chu LW, Zhu Y, Yu K et al (2008) Variants in circadian genes and prostate cancer risk: a population-based study in China. Prostate Cancer Prostatic Dis 11:342–348. doi:10.1038/sj.pcan.4501024 PubMedCrossRefGoogle Scholar
  24. 24.
    Sahar S, Sassone-Corsi P (2007) Circadian clock and breast cancer: a molecular link. Cell Cycle 6:1329–1331PubMedCrossRefGoogle Scholar
  25. 25.
    Kang TH, Sancar A (2009) Circadian regulation of DNA excision repair: implications for chrono-chemotherapy. Cell Cycle 8:1665–1667. doi:8707[pii] PubMedCrossRefGoogle Scholar
  26. 26.
    Cohen M, Lippman M, Chabner B (1978) Role of pineal gland in aetiology and treatment of breast cancer. Lancet 2:814–816. doi:10.1016/S0140-6736(78)92591-6 PubMedCrossRefGoogle Scholar
  27. 27.
    Filipski E, Li XM, Levi F (2006) Disruption of circadian coordination and malignant growth. Cancer Causes Control 17:509–514. doi:10.1007/s10552-005-9007-4 PubMedCrossRefGoogle Scholar
  28. 28.
    Shah PN, Mhatre MC, Kothari LS (1984) Effect of melatonin on mammary carcinogenesis in intact and pinealectomized rats in varying photoperiods. Cancer Res 44:3403–3407PubMedGoogle Scholar
  29. 29.
    Blask DE, Dauchy RT, Sauer LA et al (2003) Growth and fatty acid metabolism of human breast cancer (MCF-7) xenografts in nude rats: impact of constant light-induced nocturnal melatonin suppression. Breast Cancer Res Treat 79:313–320. doi:10.1023/A:1024030518065 PubMedCrossRefGoogle Scholar
  30. 30.
    Megdal SP, Kroenke CH, Laden F et al (2005) Night work and breast cancer risk: a systematic review and meta-analysis. Eur J Cancer 41:2023–2032. doi:10.1016/j.ejca.2005.05.010 PubMedCrossRefGoogle Scholar
  31. 31.
    Hansen J (2006) Risk of breast cancer after night- and shift work: current evidence and ongoing studies in Denmark. Cancer Causes Control 17:531–537. doi:10.1007/s10552-005-9006-5 PubMedCrossRefGoogle Scholar
  32. 32.
    Davis S, Mirick DK (2006) Circadian disruption, shift work and the risk of cancer: a summary of the evidence and studies in Seattle. Cancer Causes Control 17:539–545. doi:10.1007/s10552-005-9010-9 PubMedCrossRefGoogle Scholar
  33. 33.
    IARC (ed) (2006) IARC monographs on the evaluation of carcinogenic risks to humans. Preamble. International Agency for Research on Cancer, Lyon, FranceGoogle Scholar
  34. 34.
    Pronk A, Ji BT, Shu XO et al (2010) Night-shift work and breast cancer risk in a cohort of Chinese women. Am J Epidemiol 171:953–959. doi:10.1093/aje/kwq029 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Hongji Dai
    • 1
  • Lina Zhang
    • 1
  • Mingli Cao
    • 1
  • Fengju Song
    • 1
  • Hong Zheng
    • 1
  • Xiaoling Zhu
    • 1
  • Qingyi Wei
    • 2
  • Wei Zhang
    • 3
  • Kexin Chen
    • 1
  1. 1.Department of Epidemiology and BiostatisticsTianjin Medical University Cancer Hospital and InstituteTianjinPeople’s Republic of China
  2. 2.Departments of EpidemiologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  3. 3.Departments of PathologyThe University of Texas MD Anderson Cancer CenterHoustonUSA

Personalised recommendations