Abstract: Altered circadian rhythms predicted for poor survival in patients with metastatic colorectal or breast cancer. An increased incidence of cancers has been reported in flying attendants and in women working predominantly at night. To explore the contribution of circadian structure to tumor growth we ablated the 24-h rest-activity cycle and markedly altered the rhythms in body temperature, serum corticosterone and lymphocyte count in mice by complete stereotaxic destruction of the suprachiasmatic nuclei (SCN) or by subjecting the mice to experimental chronic jet-lag. Such disruption of circadian coordination significantly accelerated malignant growth in two transplantable tumor models, Glasgow osteosarcoma and Pancreatic adenocarcinoma. The mRNA expression of clock genes per2 and reverb-alpha in controls displayed significant circadian rhythms in the liver (Cosinor, p=0.006 and p=0.003, respectively) and in the tumor (p=0.04 and p<0.001, respectively). Both rhythms were suppressed in the liver and in the tumor of jet lagged mice. This functional disturbance of molecular clock resulted in down regulation of p53 and overexpression of c-Myc, two effects which may favor cancer growth. CONCLUSIONS: These results indicate that circadian system could play an important role in malignant growth control. This should be taken into consideration in cancer prevention and therapy.

Abstract: Breast cancer risk is high in industrialized societies, and increases as developing countries become more Westernized. The reasons are poorly understood. One possibility is circadian disruption from aspects of modern life, in particular the increasing use of electric power to light the night, and provide a sun-free environment during the day inside buildings. Circadian disruption could lead to alterations in melatonin production and in changing the molecular time of the circadian clock in the suprachiasmatic nuclei (SCN). There is evidence in humans that the endogenous melatonin rhythm is stronger for persons in a bright-day environment than in a dim-day environment; and the light intensity necessary to suppress melatonin at night continues to decline as new experiments are done. Melatonin suppression can increase breast tumorigenesis in experimental animals, and altering the endogenous clock mechanism may have downstream effects on cell cycle regulatory genes pertinent to breast tissue development and susceptibility. Therefore, maintenance of a solar day-aligned circadian rhythm in endogenous melatonin and in clock gene expression by exposure to a bright day and a dark night, may be a worthy goal. However, exogenous administration of melatonin in an attempt to achieve this goal may have an untoward effect given that pharmacologic dosing with melatonin has been shown to phase shift humans depending on the time of day it's given. Exogenous melatonin may therefore contribute to circadian disruption rather than alleviate it.