Guest editorial

Tumor suppressor role of genes involved in circadian clock control

Reham Hassan1[*]

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

EXCLI J 2019;18:Doc1099


In recent years evidence has accumulated that genes involved in circadian clock control play a role as tumor suppressors. Strong evidence has been presented by Broadberry and colleagues who published an article about disrupted circadian clocks in breast cancer (Broadberry et al., 2018[1]). The authors studied primary mammary epithelial cells from normal breast tissue and epithelial cells from breast carcinomas of the same patients. They transduced the cells with the luciferase clock reporter PER2:Luc, which is known to show a robust ~24 h rhythm in normal epithelial cells (Yang et al., 2017[20]). The normal epithelial breast cells showed the expected cycling. However, epithelial cells from the cancer tissue of the same individuals showed a disrupted rhythm with a much lower amplitude (Broadberry et al., 2018[1]). This study confirms previous studies presenting evidence for a tumor suppressor role of the circadian clock (Gery and Koeffler, 2010[7]; Grundy et al., 2013[9]; Fu and Lee, 2003[6]; Mormont and Lévi, 1997[15]; Filipski et al., 2002[5]). Loss of clock genes has been shown to be associated with worse prognosis in breast cancer (Cadenas et al., 2014[3]). Coordinated co-expression of clock genes (e.g. PER2-PER3 and CRY2-PER3) is maintained in estrogen receptor positive and HER2 negative carcinomas but is compromised in more aggressive tumors (Cadenas et al., 2014[3]). Genes relevant for progression of breast carcinomas have been shown to be associated with proliferation (Siggelkow et al., 2012[18]), the cellular and humoral immune system (Schmidt et al., 2008[16], 2012[17]; Heimes et al., 2017[10][11]; Lohr et al., 2013[13]; Godoy et al., 2014[8]), anti-oxidative and anti-apoptotic factors (Hellwig et al., 2016[12]; Cadenas et al., 2010[2]) and altered metabolism (Cadenas et al., 2019[4]; Marchan et al., 2017[14]; Stewart et al., 2012[19]). Although the loss of circadian clock gene expression and its association with tumor prognosis has clearly been shown, the mechanisms of their tumor suppressive effect still need to be elucidated.



1. Broadberry E, McConnell J, Williams J, Yang N, Zindy E, Leek A, et al. Disrupted circadian clocks and altered tissue mechanics in primary human breast tumours. Breast Cancer Res. 2018;20:125.
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. Cadenas C, Vosbeck S, Edlund K, Grgas K, Madjar K, Hellwig B, et al. LIPG-promoted lipid storage mediates adaptation to oxidative stress in breast cancer. Int J Cancer. 2019;145:901-15.
5. Filipski E, King VM, Li X, Granda TG, Mormont MC, Liu X, et al. Host circadian clock as a control point in tumor progression. J Natl Cancer Inst. 2002;94:690-7.
6. Fu L, Lee CC. The circadian clock: pacemaker and tumour suppressor. Nat Rev Cancer. 2003;3:350-61.
7. Gery S, Koeffler HP. Circadian rhythms and cancer. Cell Cycle. 2010;9:1097–103.
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. Grundy A, Schuetz JM, Lai AS, Janoo-Gilani R, Leach S, Burstyn I, et al. Shift work, circadian gene variants and risk of breast cancer. Cancer Epidemiol. 2013;37:606-12.
10. Heimes AS, Madjar K, Edlund K, Battista MJ, Almstedt K, Elger T, et al. Subtype-specific prognostic impact of different immune signatures in node-negative breast cancer. Breast Cancer Res Treat. 2017;165:293-300.
11. Heimes AS, Madjar K, Edlund K, Battista MJ, Almstedt K, Gebhard S, et al. Prognostic significance of interferon regulating factor 4 (IRF4) in node-negative breast cancer. J Cancer Res Clin Oncol. 2017;143:1123-31.
12. Hellwig B, Madjar K, Edlund K, Marchan R, Cadenas C, Heimes AS, et al. Epsin family member 3 and ribosome-related genes are associated with late metastasis in estrogen receptor-positive breast cancer and long-term survival in non-small cell lung cancer using a genome-wide identification and validation strategy. PLoS One. 2016;11(12):e0167585.
13. Lohr M, Edlund K, Botling J, Hammad S, Hellwig B, Othman A, et al. The prognostic relevance of tumour-infiltrating plasma cells and immunoglobulin kappa C indicates an important role of the humoral immune response in non-small cell lung cancer. Cancer Lett. 2013;333:222-8.
14. Marchan R, Büttner B, Lambert J, Edlund K, Glaeser I, Blaszkewicz M, et al. Glycerol-3-phosphate acyltransferase 1 promotes tumor cell migration and poor survival in ovarian carcinoma. Cancer Res. 2017;77:4589-601.
15. Mormont MC, Lévi F. Circadian-system alterations during cancer processes: a review. Int J Cancer. 1997;70:241-7.
16. 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.
17. 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 κ C as a compatible prognostic marker in human solid tumors. Clin Cancer Res. 2012;18:2695-703.
18. 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.
19. Stewart JD, Marchan R, Lesjak MS, Lambert J, Hergenroeder R, Ellis JK, et al. Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis. Proc Natl Acad Sci U S A. 2012;109:8155-60.
20. Yang N, Williams J, Pekovic-Vaughan V, Wang P, Olabi S, McConnell J, et al. Cellular mechano-environment regulates the mammary circadian clock. Nat. Comm. 2017;8:14287.

[*] Corresponding Author:

Reham Hassan, Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt, eMail: