Highlight report: Role of the circadian clock system in breast cancer

Ahmed Ghallab1[*]

1Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt

EXCLI J 2015;14:Doc540



It is well known that the circadian clock system coordinates physiological functions throughout the day (Dibner et al., 2010[5]; Mohawk et al., 2012[12]; Fu and Lee, 2003[6]; Hammad et al., 2013[9]). Circadian rhythms are generated by molecular feedback loops; transcriptional activators induce the expression of genes that repress their own transcription (Lowrey and Takahashi, 2011[11]). Disruption of circadian rhythms has been discussed as a possible risk factor of cancer. For example, epidemiological studies have suggested that working at night increases the risk of breast cancer (Kamdar et al., 2013[10]). However, recently a comprehensive study including 766 breast cancer patients has been published that broadens our understanding of the role of the circadian clock system in breast cancer (Cadenas et al., 2014[3]). The authors studied all known clock genes in relation to prognosis. Interestingly, loss of expression of circadian clock genes in tumour tissue was associated with a clearly higher risk to develop metastasis (Cadenas et al., 2014[3]). Recently, numerous studies have been performed to identify prognostic genes in breast cancer (e.g. Sicking et al., 2014[18][17]; Siggelkow et al., 2012[19]; Godoy et al., 2014[8]; Schmidt et al., 2008[13][14]; Cadenas, 2012;[1] Cadenas et al., 2010[2]; Ghallab, 2014[7]). However, loss of circadian clock genes seems to be of independent prognostic influence. The association of decreased circadian clock gene expression was also observed in different molecular subtypes of breast cancer (Desmedt et al., 2007[4]; Schmidt et al., 2008[13][14], 2009[16]) and was independent of established clinical factors. But the perhaps most interesting result of Cadenas et al. (2014[3]) was obtained by pairwise analysis of functionally related clock genes. PER3 and CRY2 are proteins that form dimers acting as negative feedback regulators and are known to show similar oscillation patterns. Therefore, a strong correlation between both genes can be anticipated. Indeed the authors observed strong correlations between CRY2 and PER3 in well-differentiated tumours that did not grow aggressively (Cadenas et al., 2014[3]). In contrast, the correlation between both clock genes was lost in more aggressive carcinomas. This breakdown of correlation between clock genes was also observed with loss of expression of the estrogen receptor, amplification of the oncogene HER2 and increasing histological grade (Cadenas et al., 2014[3]). In conclusion, Cadenas and colleagues have clearly shown that loss of clock gene expression and particularly the breakdown of coordinated co-expression of clock genes is associated with worse prognosis and dedifferentiation, a feature so far unknown in breast cancer.



1. Cadenas C. Prognostic signatures of breast cancer: Perous molecular subtypes and Schmidts metagenes. EXCLI J. 2012;11:204-7.
2. Cadenas C, Franckenstein D, Schmidt M, Gehrmann M, Hermes M, Geppert B, et al. Role of thioredoxin reductase 1 and thioredoxin interacting protein in prognosis of breast cancer. Breast Cancer Res. 2010;12(3):R44.
3. Cadenas C, van de Sandt L, Edlund K, Lohr M, Hellwig B, Marchan R, et al. Loss of circadian clock gene expression is associated with tumor progression in breast cancer. Cell Cycle. 2014;13:3282-91.
4. Desmedt C, Piette F, Loi S, Wang Y, Lallemand F, Haibe-Kains B, et al. Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series. Clin Cancer Res. 2007;13: 3207-14.
5. Dibner C, Schibler U, Albrecht U. The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu Rev Physiol. 2010;72:517-49.
6. Fu L, Lee CC. The circadian clock: pacemaker and tumour suppressor. Nat Rev Cancer. 2003;3:350-61.
7. Ghallab A. Highlights in tumor metabolome research: choline metabolism influences integrin expression and supports cell attachment. EXCLI J. 2014;13:856-8.
8. Godoy P, Cadenas C, Hellwig B, Marchan R, Stewart J, Reif R, et al. Interferon-inducible guanylate binding protein (GBP2) is associated with better prognosis in breast cancer and indicates an efficient T cell response. Breast Cancer. 2014;21:491-9.
9. Hammad S, Marchan R, Hengstler JG. Cutting-edge topics in research on animal sciences. (Editorial). J Exp Appl Anim Sci. 2013;1:1-3.
10. Kamdar BB, Tergas AI, Mateen FJ, Bhayani NH, Oh J. Night-shift work and risk of breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat. 2013;138:291-301.
11. Lowrey PL, Takahashi JS. Genetics of circadian rhythms in Mammalian model organisms. Adv Genet. 2011;74:175-230.
12. Mohawk JA, Green CB, Takahashi JS. Central and peripheral circadian clocks in mammals. Annu Rev Neurosci. 2012;35:445-62.
13. Schmidt M, Böhm D, von Törne C, Steiner E, Puhl A, Pilch H, et al. The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res. 2008;68:5405-13.
14. Schmidt M, Hasenclever D, Schaeffer M, Boehm D, Cotarelo C, Steiner E, et al. Prognostic effect of epithelial cell adhesion molecule overexpression in untreated node-negative breast cancer. Clin Cancer Res. 2008;14:5849-55.
15. Schmidt M, Hellwig B, Hammad S, Othman A, Lohr M, Chen Z, et al. A comprehensive analysis of human gene expression profiles identifies stromal immunoglobulin kappa C as a compatible prognostic marker in human solid tumors. Clin Cancer Res. 2012;18:2695-703.
16. Schmidt M, Hengstler JG, von Törne C, Koelbl H, Gehrmann MC. Coordinates in the universe of node-negative breast cancer revisited. Cancer Res. 2009;69: 2695-8.
17. Sicking I, Edlund K, Wesbuer E, Weyer V, Battista MJ, Lebrecht A, et al. Prognostic influence of pre-operative C-reactive protein in node-negative breast cancer patients. PLoS One. 2014b;9(10):e111306.
18. Sicking I, Rommens K, Battista MJ, Böhm D, Gebhard S, Lebrecht A, et al. Prognostic influence of cyclooxygenase-2 protein and mRNA expression in node-negative breast cancer patients. BMC Cancer. 2014;14:952.
19. Siggelkow W, Boehm D, Gebhard S, Battista M, Sicking I, Lebrecht A, et al. Expression of aurora kinase A is associated with metastasis-free survival in node-negative breast cancer patients. BMC Cancer. 2012;12:562.

[*] Corresponding Author:

Ahmed Ghallab, Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt, eMail: ghallab@vet.svu.edu.eg