Thursday, July 15, 2021
7/15/2021
Project Summary/Abstract The increased risk of breast cancer due to working nights or rotating shifts has been attributed to disruption of circadian rhythms, chronic sleep loss, nighttime light exposure, melatonin suppression, and chronic stress and fatigue. Because shift work can alter these variables simultaneously, human studies have been unable to determine the relative contributions of these variables to increased cancer risk. Several studies in rodent cancer models have purported to show that circadian rhythm disruption increases cancer progression. Unfortunately, all of the methods used to disrupt rhythms also produce chronic sleep loss, melatonin suppression, and increased stress hormones, each of which is capable of promoting tumor growth and proliferation. Therefore, the results of those animal studies cannot be strictly attributed to circadian disruption. To date, there is not a single animal study that has isolated the effects of circadian disruption on cancer without these confounds. We believe that a new animal model is needed to address this problem. We can eliminate these confounds and directly address the role of the circadian system in tumor development and progression by employing a new animal model, the circadian-arrhythmic Siberian hamster (Phodopus sungorus). This model was developed in our laboratory over the past 20 years and is uniquely suited for this project because circadian timing can be eliminated without impairing sleep or inducing stress. Circadian timing is eliminated by a single photic treatment that we have termed, the Disruptive Phase Shift (DPS) protocol. This protocol eliminates the need to ablate the SCN or alter gene expression, thus leaving the animals arrhythmic, but neurologically and genetically intact. Thus, we can directly evaluate the contribution of circadian disruption to tumor development and progression by completely shutting off circadian timing, and without impairing sleep or inducing stress. We have chosen to investigate the role of circadian disruption in a breast cancer model where tumors are induced by the carcinogen N-methyl-N-nitrosurea (NMU;; MNU). This is a widely used and well-established model of human breast cancer that works well in our hamsters. NMU is highly specific for mammary tissue and tumors can be induced by a single injection of the carcinogen. We propose to: 1) definitively establish whether the loss of circadian timing (without impairing sleep) increases tumor development, 2) determine whether melatonin suppression that accompanies circadian-arrhythmia increases tumor development, and 3) use a scheduled feeding paradigm to ameliorate the effects of circadian arrhythmia on tumor development.
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