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Oncotarget. 2017 May 16;8(20):32752-32768. doi: 10.18632/oncotarget.15678.

Uncoupling genotoxic stress responses from circadian control increases susceptibility to mammary carcinogenesis.

Fang M1,2,3,4, Ohman Strickland PA1,3,4, Kang HG5, Zarbl H1,2,3,4.

Author information

1
School of Public Health, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
2
Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
3
NIEHS Center for Environmental Exposures and Disease, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
4
Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
5
Veterinary Drugs & Biologics Division, Animal and Plant Quarantine Agency, Gimcheon-si, Gyeongsangbuk-do, Republic of Korea.

Abstract

We previously demonstrated that chemopreventive methylselenocysteine (MSC) prevents N-Nitroso-N-methylurea (NMU)-induced mammary carcinogenesis in the susceptible Fischer 344 (F344) rats by enhancing NAD+-dependent SIRT1 activity, restoring circadian expression of Period 2 (Per2) and circadian controlled genes. Here, we show that compared to the genetically resistant Copenhagen (COP) rat strain, mammary glands of the F344 rats have a 4-hour phase delay in circadian expression of Per2. Consequently, F344 rats failed to increase SIRT1 activity and circadian expression of Per2 and DDRR genes after exposure to NMU. Exposure of COP rats to NMU had the opposite effect, enhancing SIRT1 activity, increasing circadian expression of Per2 and DDRR genes. Significantly, SIRT1 activity and circadian expression of Per2 and DDRR genes in NMU-treated F344 rats on a chemopreventive regimen of MSC approximated those in NMU-treated COP rats. These results indicated that COP rats have an increased capacity to maintain NAD+-dependent SIRT1 activity under genotoxic stress. This contention was supported by increased stability of the period and phase of circadian locomotor activity in COP vs F344 rats exposed to changing light conditions. The increased sensitivity and rapid response of COP to changing light were correlated with the enhanced circadian response of this strain to carcinogen. Disturbance of circadian rhythm by jet lag also disrupted circadian expression of Per2 and DDRR genes, and accelerated mammary tumorigenesis in rodent models. These results suggested that uncoupling of DDRR responses from circadian control by environmental stresses and endogenous factors increases susceptibility to mammary carcinogenesis, possibly by inducing a promutagenic state.

KEYWORDS:

DNA damage response and repair; Period 2; SIRT1; circadian rhythm; genetic susceptibility

PMID:
28427145
PMCID:
PMC5464825
DOI:
10.18632/oncotarget.15678
[Indexed for MEDLINE]
Free PMC Article

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