Circadian rhythm of tumor promotion in the two-stage model of mouse tumorigenesis

The question of whether cancer risk is influenced by time-of-day exposure to potentially carcinogenic agents was approached in this study by exposing mouse skin to a single initiating dose of 7,12-dimethylbenz [∀-]anthracene, followed by a 12 week regime of bi-weekly skin treatments with the tumor promoter, 12-0-tetradecanoyl-phorbol acetate (TPA), given at four different circadian clock times (CCTs). Tumor incidence, average number of tumors per mouse and tumor size showed a dominant circadian component with an acrophase occurring at 23:00 h CCT. Pre-treatment with all trans-retinoic acid, prior to bi-weekly TPA promotion, reduced tumor incidence, average number and size of tumors per animal by greater than 80%, but did not suppress the underlying circadian rhythm of sensitivity to TPA-induced tumor formation.