Circadian clock disruptions and the risk of cancer

Figures & data

Figure 1. Association between circadian clock and cell cycle. CLOCK:BMAL1 complex regulates directly the WEE1 and MYC signaling pathway, influencing cell proliferation. CRY and PER1 participate in DNA damage repair mechanisms. CRY is directly involved in the ATR:CHK1 DNA damage repair complex by binding with TIM. PER1 on the other hand participates in the ATM:CHK2 DNA damage repair complex. DEC2 regulates VEGF, thus influencing angiogenesis (38,48,49,56,63,64).

Table I. Human circadian clock gene variants associated with cancers. References are given in the brackets.

Gene	Gene abbreviation	Cancer (reference)	Mutation	Possible mechanism leading to cancer
Circadian locomoter output cycles kaput	CLOCK	Breast cancer (42,45)	rs7698022, rs11133391, rs11932595, 1048004, and rs3805151	Stimulated cell proliferation, altered hormone signaling pathway regulation
		Prostate cancer (41)	rs11133373
Cryptochrome1	CRY1	Breast cancer (45)	rs1056560	Altered hormone signaling pathway regulation
		Prostate cancer (41)	rs12315175
Cryptochrome2	CRY2	Breast cancer (43)	rs11038689, rs7123390, and rs1401417	Hormone stimulation
		Non-Hodgkin lymphoma (34)	rs11038689, rs7123390, and rs1401417	Altered interleukine, MHC, and chemokine gene expression
		Prostate cancer (39,41)	rs2292912, rs1401417	Stimulated cell proliferation, altered hormone signaling pathway regulation
Neuronal PAS domain protein 2	NPAS2	Breast cancer (40,44)	Ala394Thr polymorphism (rs2305160)	Hormone stimulation
		Non-Hodgkin lymphoma (33)	Ala394Thr polymorphism (rs2305160)	Impaired DNA damage response
		Prostate cancer (39,41)	rs1369481, rs895521, and rs17024926	Impaired DNA damage response
Period1	PER1	Prostate cancer (41)	rs885747 and rs2289591	Impaired DNA damage response
Period2	PER2	Prostate cancer (41)	rs7602358	Impaired DNA damage response
Period3	PER3	Breast cancer (38)	Hetero- + homozygous 5-repeat alleles	Stimulated cell proliferation, hormone stimulation
		Prostate cancer (41)	rs1012477
Aryl hydrocarbon receptor nuclear translocator-like	ARNTL (BMAL1)	Prostate cancer (41)	rs7950226	Hormone stimulation
Casein kinase 1, epsilon	CSNK1E	Prostate cancer (41)	rs1534891	Stimulated cell proliferation

Zhu Y, Brown HN, Zhang Y, Stevens RG, Zheng T. Period3 structural variation: a circadian biomarker associated with breast cancer in young women. Cancer Epidemiol Biomarkers Prev. 2005;14:268–70.

 PubMed Web of Science ®Google Scholar

Sahar S, Sassone-Corsi P. Metabolism and cancer: the circadian clock connection. Nat Rev Cancer. 2009;9:886–96.

 PubMed Web of Science ®Google Scholar

Reddy AB, O’Neill JS. Healthy clocks, healthy body, healthy mind. Trends Cell Biol. 2010;20:36–44.

 PubMed Web of Science ®Google Scholar

Sancar A, Lindsey-Boltz LA, Kang TH, Reardon JT, Lee JH, Ozturk N. Circadian clock control of the cellular response to DNA damage. FEBS Lett. 2010;584:2618–25.

 PubMed Web of Science ®Google Scholar

Guess J, Burch JB, Ogoussan K, Armstead CA, Zhang H, Wagner S, . Circadian disruption, Per3, and human cytokine secretion. Integr Cancer Ther. 2009;8:329–36.

 PubMed Web of Science ®Google Scholar

Sato F, Bhawal UK, Kawamoto T, Fujimoto K, Imaizumi T, Imanaka T, . Basic-helix-loop-helix (bHLH) transcription factor DEC2 negatively regulates vascular endothelial growth factor expression. Genes Cells. 2008;13:131–44.

 PubMed Web of Science ®Google Scholar

Hoffman AE, Yi CH, Zheng T, Stevens RG, Leaderer D, Zhang Y, . CLOCK in breast tumorigenesis: genetic, epigenetic, and transcriptional profiling analyses. Cancer Res. 2010;70:1459–68.

 PubMed Web of Science ®Google Scholar

Dai H, Zhang L, Cao M, Song F, Zheng H, Zhu X, . The role of polymorphisms in circadian pathway genes in breast tumorigenesis. Breast Cancer Res Treat. 2011;127: 531–40.

 PubMed Web of Science ®Google Scholar

Zhu Y, Stevens RG, Hoffman AE, Fitzgerald LM, Kwon EM, Ostrander EA, . Testing the circadian gene hypothesis in prostate cancer: a population-based case-control study. Cancer Res. 2009;69:9315–22.

 PubMed Web of Science ®Google Scholar

Hoffman AE, Zheng T, Yi CH, Stevens RG, Ba Y, Zhang Y, . The core circadian gene Cryptochrome 2 influences breast cancer risk, possibly by mediating hormone signaling. Cancer Prev Res (Phila). 2010;3:539–48.

 PubMed Web of Science ®Google Scholar

Hoffman AE, Zheng T, Stevens RG, Ba Y, Zhang Y, Leaderer D, . Clock-cancer connection in non-Hodgkin's lymphoma: a genetic association study and pathway analysis of the circadian gene cryptochrome 2. Cancer Res. 2009;69: 3605–13.

 PubMed Web of Science ®Google Scholar

Chu LW, Zhu Y, Yu K, Zheng T, Yu H, Zhang Y, . Variants in circadian genes and prostate cancer risk: a population-based study in China. Prostate Cancer Prostatic Dis. 2008;11:342–8.

 Google Scholar

Zhu Y, Stevens RG, Leaderer D, Hoffman A, Holford T, Zhang Y, . Non-synonymous polymorphisms in the circadian gene NPAS2 and breast cancer risk. Breast Cancer Res Treat. 2008;107:421–5.

 PubMed Web of Science ®Google Scholar

Yi C, Mu L, de la Longrais IA, Sochirca O, Arisio R, Yu H, . The circadian gene NPAS2 is a novel prognostic biomarker for breast cancer. Breast Cancer Res Treat. 2010;120:663–9.

 PubMed Web of Science ®Google Scholar

Zhu Y, Leaderer D, Guss C, Brown HN, Zhang Y, Boyle P, . Ala394Thr polymorphism in the clock gene NPAS2: a circadian modifier for the risk of non-Hodgkin's lymphoma. Int J Cancer. 2007;120:432–5.

 PubMed Web of Science ®Google Scholar