Period genes ( Per2, Per1) are essential circadian clock genes. They also function as negative growth regulators. Per2 mutant mice show de novo and radiation-induced epithelial
hyperplasia,
tumors, and an abnormal DNA damage response. Human
tumors show Period gene mutations or decreased expression. Other murine clock gene mutations are not associated with a
tumor prone phenotype. Shift work and nocturnal light exposure are associated with circadian clock disruption and with increased
cancer risk. The mechanisms responsible for the connection between the circadian clock and
cancer are not well defined. We propose that circadian disruption per se is not uniformly
tumor promoting and the mechanisms for
tumor promotion by specific circadian clock disturbances will differ dependent upon the genes and pathways involved. We propose that Period clock gene mutations promote
tumorigenesis by unique molecular pathways. Per2 and Per1 modulate
beta-catenin and cell proliferation in colon and non-
colon cancer cells. Per2 mutation increases intestinal
beta-catenin levels and colon
polyp formation. Per2 mutation also increases Apc(Min/+)-mediated intestinal and
colonic polyp formation. Intestinal
tumorigenesis per se may also alter clock function as a result of increased
beta-catenin destabilizing PER2
protein. Levels and circadian rhythm of PER2 in Apc(Min/+) mouse intestine are markedly decreased, and selective abnormalities in intestinal clock gene and clock-controlled gene expression are seen. We propose that
tumor promotion by loss of PERIOD
clock proteins is unique to these clock genes as a result of altered
beta-catenin signaling and DNA damage response.
PERIOD proteins may offer new targets for
cancer prevention and control.