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Breast Cancer Research and Treatment

, Volume 91, Issue 1, pp 47–60 | Cite as

Daily coordination of cancer growth and circadian clock gene expression

  • Shaojin You
  • Patricia A. Wood
  • Yin Xiong
  • Minoru Kobayashi
  • Jovelyn Du-Quiton
  • William J. M. HrusheskyEmail author
Report

Abstract

Background.Circadian coordination in mammals is accomplished, in part, by coordinate, rhythmic expression of a series of circadian clock genes in the central clock within the suprachiasmatic nuclei (SCN) of the hypothalamus. These same genes are also rhythmically expressed each day within each peripheral tissue.

Methods.We measured tumor size, tumor cell cyclin E protein, tumor cell mitotic index, and circadian clock gene expression in liver and tumor cells at six equispaced times of day in individual mice of a 12-h light, 12-h dark schedule.

Results.We demonstrate that C3HFeJ/HeB mice with transplanted syngeneic mammary tumor maintain largely normal circadian sleep/activity patterns, and that the rate of tumor growth is highly rhythmic during each day. Two daily 2.5-fold peaks in cancer cell cyclin E protein, a marker of DNA synthesis, are followed by two daily up-to-3-fold peaks in cancer cell mitosis (one minor, and one major peak). These peaks are, in turn, followed by two prominent daily peaks in tumor growth rate occurring during mid-sleep and the second, during mid-activity. These data indicate that all therapeutic targets relevant to tumor growth and tumor cell proliferation are ordered in tumor cells within each day. The daily expression patterns of the circadian clock genes Bmal1, mPer1, and mPer2, remain normally circadian coordinated in the livers of these tumor bearing mice. Bmal1 gene expression remains circadian rhythmic in cancer cells, although damped in amplitude, with a similar circadian pattern to that in normal hepatocytes. However, tumor cell mPer1 and mPer2 gene expression patterns fail to maintain statistically significant daily rhythms.

Conclusion. We conclude that, if core circadian clock gene expression is essential to gate tumor cell proliferation within each day, then there may be substantial redundancy in this timing system. Alternatively, the daily ordering of tumor cell clock gene expression may not be essential to the daily gating of cancer cell DNA synthesis, mitosis and growth. This would indicate that host central SCN-mediated neuro–humoro-behavioral controls and/or daily light-induced changes in melatonin or peripherally-induced rhythms such as those resulting from feeding, may be adequate for the daily coordination of cancer cell expression of proliferation related therapeutic targets.

Keywords

cancer cancer growth cancer proliferation circadian clock controlled genes core clock genes 

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References

  1. 1.
    Pittendrigh, CS. 1993Temporat organization: reflections of a Darwinian clock-watcherAnn Rev Physiol551654CrossRefGoogle Scholar
  2. 2.
    Vitaterna, MH, King, DP, Chang, AM, Kornhauser, JM, Lowrey, PL, McDonald, JD, Dove, WF, Pinto, LH, Turek, FW, Takahashi, JS. 1994Mutagenesis and mapping of a mouse gene, clock, essential for circadian behaviorScience264719725PubMedGoogle Scholar
  3. 3.
    King, DP, Zhao, Y, Sangoram, AM, Wilsbacher, LD, Tanaka, M, Antoch, MP, Steeves, TD, Vitaterna, MH, Kornhauser, JM, Lowrey, PL,  et al. 1997Positional cloning of the mouse circadian clock geneCell89641653CrossRefPubMedGoogle Scholar
  4. 4.
    Tei, H, Okamura, H, Shigeyoshi, Y, Fukuhara, C, Ozawa, R, Hirose, M, Sakaki, Y. 1997Circadian oscillation of a mammalian homologue of the Drosophila period geneNature389512516CrossRefPubMedGoogle Scholar
  5. 5.
    Sun, ZS, Albrecht, U, Zhuchenko, O, Bailey, J, Eichele, G, Lee, CC. 1997RIGUI, a putative mammalian ortholog of the Drosophila period geneCell9010031011CrossRefPubMedGoogle Scholar
  6. 6.
    Gekakis, N, Staknis, D, Nguyen, HB, Davis, FC, Wilsbacher, LD, King, DP, Takahashi, JS, Weitz, CJ. 1998Role of the CLOCK protein in the mammalian circadian mechanismScience28015641569CrossRefPubMedGoogle Scholar
  7. 7.
    Sangoram, AM, Saez, L, Antoch, MP, Gekakis, N, Staknis, D, Whiteley, A, Fruechte, EM, Vitaterna, MH, Shimomura, K, King, DP,  et al. 1998Mammalian circadian autoregulatory loop: a timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcriptionNeuron2111011113CrossRefPubMedGoogle Scholar
  8. 8.
    Davidson, AJ, Poole, AS, Yamazaki, S, Menaker, M. 2003Is the food-entrainable circadian oscillator in the digestive system?Genes Brain Behav23239CrossRefPubMedGoogle Scholar
  9. 9.
    Stokkan, KA, Yamazaki, S, Tei, H, Sakaki, Y, Menaker, M 2001Entrainment of the circadian clock in the liver by feedingScience291490493CrossRefPubMedGoogle Scholar
  10. 10.
    Zylka, MJ, Shearman, LP, Weaver, DR, Reppert, SM. 1998Three period homologs in mammals: differential light responses in the suprachiasmatic circadian clock and oscillating transcripts outside of brainNeuron2011031110CrossRefPubMedGoogle Scholar
  11. 11.
    Sakamoto, K, Nagase, T, Fukui, H, Horikawa, K, Okada, T, Tanaka, H, Sato, K, Miyake, Y, Ohara, O, Kako, K,  et al. 1998Multitissue circadian expression of rat period homolog (rPer2) mRNA is governed by the mammalian circadian clock, the suprachiasmatic nucleus in the brainJ Biol Chem2732703927042CrossRefPubMedGoogle Scholar
  12. 12.
    Scheving, LE. 1959Mitotic activity in the human epidermisAnat Rec135719CrossRefPubMedGoogle Scholar
  13. 13.
    Smaaland, R, Laerum, O, Lote, K, Sletvold, O, Sothern, R, Bjerknes, R. 1991DNA synthesis in human bone marrow is circadian stage dependentBlood7726032611PubMedGoogle Scholar
  14. 14.
    Buchi, K, Moore, J, Hrushesky, W, Sothern, R, Rubin, N. 1991Circadian rhythm of cellular proliferation in the human rectal mucosaGastroenterology101410415PubMedGoogle Scholar
  15. 15.
    Scheving, LE, Burns, ER, Pauly, JE, Halberg, F, Haus, E. 1977Survival and cure of leukemic mice after circadian optimization of treatment with cyclophosphamide and 1-beta-D-arabinofuranosylcytosineCancer Res3736483655PubMedGoogle Scholar
  16. 16.
    Haus, E, Halberg, F, Scheving, L, Cardoso, S, Kuhl, JFW, Sothern, R, Shiotsuka, R, Hwang, D, Pauli, SE. 1972Increased tolerance of mice to arabinosylcytosine given on schedule adjusted to circadian systemScience1778082PubMedGoogle Scholar
  17. 17.
    Hrushesky, WJ, Bjarnason, GA. 1993Circadian cancer therapyJ Clin Oncol1114031417PubMedGoogle Scholar
  18. 18.
    Hrushesky, WJ. 1985Circadian timing of cancer chemotherapyScience2287375PubMedGoogle Scholar
  19. 19.
    Lévi, F, Zidani, R, Misset, J-L. 1997Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancerLancet360681686CrossRefGoogle Scholar
  20. 20.
    Levi, FA, Zidani, R, Vannetzel, JM, Perpoint, B, Focan, C, Faggiuolo, R, Chollet, P, Garufi, C, Itzhaki, M, Dogliotti, L,  et al. 1994Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trialJ Natl Cancer Inst8616081617PubMedGoogle Scholar
  21. 21.
    Wood, PA, Hrushesky, WJ. 1996Circadian rhythms and cancer chemotherapyCrit Rev Eukaryot Gene Expr6299343PubMedGoogle Scholar
  22. 22.
    Wood, PA, Hrushesky, WJ, Klevecz, R. 1998Distinct circadian time structures characterize myeloid and erythroid progenitor and multipotential cell clonogenicity as well as marrow precursor proliferation dynamicsExp Hematol26523533PubMedGoogle Scholar
  23. 23.
    Lincoln, D, Hrushesky, W, Wood, P. 2000Circadian organization of thymidylate synthase activity in normal tissues: a possible basis for 5-fluorouracil chronotherapeutic advantageInt J Cancer88479485CrossRefPubMedGoogle Scholar
  24. 24.
    Bjarnason, G, Jordan, R, Wood, P, Li, Q, Lincoln, D, Sothern, R, Hrushesky, W, Ben-David, Y. 2001Circadian expression of clock genes in human oral mucosa and skin: association with specific cell cycle phasesAmer J Pathol15817931801Google Scholar
  25. 25.
    Sothern, RB, Levi, F, Haus, E, Halberg, F, Hrushesky, WJM. 1989Control of a murine plasmacytoma with doxorubicin-cisplatin: dependence on circadian stage of treatmentJ Natl Cancer Inst81135145PubMedGoogle Scholar
  26. 26.
    Hrushesky, WJ, Lannin, D, Haus, E. 1998Evidence for an ontogenetic basis for circadian coordination of cancer cell proliferationJ Natl Cancer Inst9014801484CrossRefPubMedGoogle Scholar
  27. 27.
    Smaaland, R, Lote, K, Sothern, RB, Laerum, OD. 1993DNA synthesis and ploidy in non-Hodgkin’s lymphomas demonstrate intrapatient variation depending on circadian stage of cell samplingCancer Res5331293138PubMedGoogle Scholar
  28. 28.
    Klevecz, RR, Shymko, RM, Blumenfeld, D, Braly, PS. 1987Circadian gating of S phase in human ovarian cancerCancer Res4762676271PubMedGoogle Scholar
  29. 29.
    Fisher, B, Fisher, E. 1959Experimental evidence in support of the dormant tumor cell scienceScience130918919PubMedGoogle Scholar
  30. 30.
    Hrushesky, WJM, Bluming, AZ, Gruber, SA, Sothern, RB. 1989Menstrual influence on surgical cure of breast cancerLancet ii:949949952CrossRefGoogle Scholar
  31. 31.
    You S, Li W, Kobayashi M, Xiong Y, Hrushesky WJ, Wood PA. (2004). Creation of a stable mammary tumor cell line that maintains fertility cycle tumor biology of the parent tumor. In Vitro Cell De Biol Anim 40(3)Google Scholar
  32. 32.
    Wells, W, Rainer, RO, Memoli, VA. 1992Basic principles of image processingAm J Clin Pathol98493501PubMedGoogle Scholar
  33. 33.
    You, S, Yao, K, Cao, Y. 1996Latency of Epstein-Barr virus and its relationship to nasopharyngeal carcinomasZhonghua Zhong Liu Za Zhi182326PubMedGoogle Scholar
  34. 34.
    Hori, K, Zhang, QH, Li, HC, Saito, S. 1995Variation of growth rate of a rat tumour during a light–dark cycle: correlation with circadian fluctuations in tumour blood flowBr J Cancer7111631168PubMedGoogle Scholar
  35. 35.
    Bevilacqua, P, Barbareschi, M, Verderio, P, Boracchi, P, Caffo, O, Dalla Palma, P, Meli, S, Weidner, N, Gasparini, G. 1995Prognostic value of intratumoral microvessel density, a measure of tumor angiogenesis, in node-negative breast carcinoma–results of a multiparametric studyBreast Cancer Res Treat36205217CrossRefPubMedGoogle Scholar
  36. 36.
    Laforga, J, Aranda, FI. 2000Angiogenic Index: a new method for assessing microvascularity in breast carcinoma with possible prognostic implicationsBreast J6103107CrossRefPubMedGoogle Scholar
  37. 37.
    Koff, A, Giordano, A, Desai, D, Yamashita, K, Harper, JW, Elledge, S, Nishimoto, T, Morgan, DO, Franza, BR, Roberts, JM. 1992Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycleScience25716891694PubMedGoogle Scholar
  38. 38.
    Koff, A, Cross, F, Fisher, A, Schumacher, J, Leguellec, K, Philippe, M, Roberts, JM. 1991Human cyclin E, a new cyclin that interacts with two members of the CDC2 gene familyCell6612171228CrossRefPubMedGoogle Scholar
  39. 39.
    Ohtsubo, M, Theodoras, AM, Schumacher, J, Roberts, JM, Pagano, M. 1995Human cyclin E, a nuclear protein essential for the G1-to-S phase transitionMol Cell Biol1526122624PubMedGoogle Scholar
  40. 40.
    Abizaid, A, Mezei, G, Horvath, TL. 2004Estradiol enhances light-induced expression of transcription factors in the SCNBrain Res10103544CrossRefPubMedGoogle Scholar
  41. 41.
    Hara, R, Wan, K, Wakamatsu, H, Aida, R, Moriya, T, Akiyama, M, Shibata, S. 2001Restricted feeding entrains liver clock without participation of the suprachiasmatic nucleusGenes Cells6269278CrossRefPubMedGoogle Scholar
  42. 42.
    Jin, X, Shearman, LP, Weaver, DR, Zylka, MJ, Vries, GJ, Reppert, SM. 1999A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clockCell965768CrossRefPubMedGoogle Scholar
  43. 43.
    Lee, C, Etchegaray, JP, Cagampang, FR, Loudon, AS, Reppert, SM. 2001Posttranslational mechanisms regulate the mammalian circadian clockCell107855867CrossRefPubMedGoogle Scholar
  44. 44.
    Oishi, K, Fukui, H, Ishida, N. 2000Rhythmic expression of BMAL1 mRNA is altered in clock mutant mice: differential regulation in the suprachiasmatic nucleus and peripheral tissuesBiochem Biophys Res Commun268164171CrossRefPubMedGoogle Scholar
  45. 45.
    Takata, M, Burioka, N, Ohdo, S, Takane, H, Terazono, H, Miyata, M, Sako, T, Suyama, H, Fukuoka, Y, Tomita, K,  et al. 2002Daily expression of mRNAs for the mammalian clock genes Per2 and clock in mouse suprachiasmatic nuclei and liver and human peripheral blood mononuclear cellsJpn J Pharmacol90263269CrossRefPubMedGoogle Scholar
  46. 46.
    Mormont, M, Prins, J, Levi, F. 1996Study of circadian rhythm of activity by actometry: preliminary results in 30 patients with metastatic colorectal cancerPath Biol3165171Google Scholar
  47. 47.
    Sephton, SE, Sapolsky, RM, Kraemer, HC, Spiegel, D. 2000Diurnal cortisol rhythm as a predictor of breast cancer survivalJ Natl Cancer Inst929941000CrossRefPubMedGoogle Scholar
  48. 48.
    Hori, K, Zhang, Q-H, Li, H-C, Saito, S. 1995Variation of growth rate of a rat tumour during a light–dark cycle: correlation with circadian fluctuations in tumour blood flowBr J of Cancer7111631168Google Scholar
  49. 49.
    Hori, K, Suzuki, M, Tanda, S, Saito, S, Shinozaki, M, Zhang, QH. 1992Circadian variation of tumor blood flow in rat subcutaneous tumors and its alteration by angiotensin II-induced hypertensionCancer Res52912916PubMedGoogle Scholar
  50. 50.
    Voutilainen, A. 1953Über die 24-stunden-rhythmik der mitozfrequenz in malignen tumorenActa Path Microb Scan991104Google Scholar
  51. 51.
    Tähti, E. 1956Studies of the effect of X-irradiation on 24 hour variations in the mitotic activity in human malignant tumoursActa Path Microbiol Scand117161Google Scholar
  52. 52.
    Nash, RE, Llanos, JM. 1971Twenty-four-hour variations in DNA synthesis of a fast-growing and a slow-growing hepatoma: DNA synthesis rhythm in hepatomaJ Natl Cancer Inst4710071012PubMedGoogle Scholar
  53. 53.
    Burns, E, Scheving, L, Tsai, T. 1979Circadian rhythms in DNA synthesis and mitosis in normal mice and in mice bearing the Lewis lung carcinomaEur J Cancer15233242PubMedGoogle Scholar
  54. 54.
    McGowan, CH, Russell, P. 1995Cell cycle regulation of human WEE1Embro J1421662175Google Scholar
  55. 55.
    Jin, P, Gu, Y, Morgan, DO. 1996Role of inhibitory CDC2 phosphorylation in radiation-induced G2 arrest in human cellsJ Cell Biol134963970CrossRefPubMedGoogle Scholar
  56. 56.
    Watanabe, N, Broome, M, Hunter, T. 1995Regulation of the human WEE1Hu CDK tyrosine 15-kinase during the cell cycleEmbro J1418791891Google Scholar
  57. 57.
    Sherr, CJ, Roberts, JM. 1995Inhibitors of mammalian G1 cyclin-dependent kinasesGenes Dev911491163PubMedGoogle Scholar
  58. 58.
    Tchou, WW, Rom, WN, Tchou-Wong, KM. 1996Novel form of p21(WAF1/CIP1/SDI1) protein in phorbolester-induced G2/M arrestJ Biol Chem2712955629560CrossRefPubMedGoogle Scholar
  59. 59.
    Badie, C, Bourhis, J, Sobczak-Thepot, J, Haddada, H, Chiron, M, Janicot, M, Janot, F, Tursz, T, Vassal, G. 2000p53-dependent G2 arrest associated with a decrease in cyclins A2 and B1 levels in a human carcinoma cell lineBr J Cancer82642650CrossRefPubMedGoogle Scholar
  60. 60.
    Matsuo, T, Yamaguchi, S, Mitsui, S, Emi, A, Shimoda, F, Okamura, H. 2003Control mechanism of the circadian clock for timing of cell division in vivo Science302255259CrossRefPubMedGoogle Scholar
  61. 61.
    Fu, L, Pelicano, H, Liu, J, Huang, P, Lee, CC. 2002The circadian gene period2 plays an important role in tumor suppression and DNA damage response in vivo Cell1114150CrossRefPubMedGoogle Scholar
  62. 62.
    Bjarnason, GA, Jordan, RC, Sothern, RB. 1999Circadian variation in the expression of cell-cycle proteins in human oral epitheliumAm J Pathol154613622PubMedGoogle Scholar
  63. 63.
    You, S, Xiong, Y, Kobayashi, M, Wood, P, Bickley, S, Simu, M, Quiton, J, Hrushesky, WJ. 2003Tumor cell circadian clock genes are rhythmically expressed in coordination with rhythmic circadian growth and thereby may represent new therapeutic targetsClin Cancer Res96126sGoogle Scholar
  64. 64.
    Darlington, TK, Lyons, LC, Hardin, PE, Kay, SA. 2000The period E-box is sufficient to drive circadian oscillation of transcription in vivo J Biol Rhythms15462471CrossRefPubMedGoogle Scholar
  65. 65.
    Farina, A, Gaetano, C, Crescenzi, M, Puccini, F, Manni, I, Sacchi, A, Piaggio, G. 1996The inhibition of cyclin B1 gene transcription in quiescent NIH3T3 cells is mediated by an E-boxOncogene1312871296PubMedGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Shaojin You
    • 1
  • Patricia A. Wood
    • 1
  • Yin Xiong
    • 1
  • Minoru Kobayashi
    • 1
  • Jovelyn Du-Quiton
    • 1
  • William J. M. Hrushesky
    • 1
    • 2
    Email author
  1. 1.Medical Chronobiology Laboratory, Dorn Research Institute, WJB Dorn VA Medical Center and the School of MedicineUniversity of South CarolinaColumbiaUSA
  2. 2.WJB Dorn Veterans Affairs Medical Center (151)6439 Garners Ferry RoadColumbia

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