The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 230

by either constant light exposure or pinealectomy increases spontaneous and
carcinogen-induced mammary gland and hepatocellular carcinogenesis in
rodents. 114-116 Similar experiments conducted in recent years have also shown
that disruption of circadian homeostasis by a short period of back-and-forth or
consecutive phase-advance shifts of environmental light cues, or by constant
light exposure significantly accelerates tumor growth in animals. 117-121 Com-
pared to sham-operated animals, mice lacking a central clock due to surgical
ablation of the SCN were unable to maintain circadian rhythmicity in loco-
motor activity, body temperature, and immune function. This loss of circa-
dian homeostasis in SCN-lesioned mice is coupled with a significant
decrease in survival time due to the increased rate of tumor growth compared
to control tumor-bearing mice with an intact SCN. 122 Together, these studies
agree with the findings from human studies in that circadian dysfunction
increases the risk of cancer by demonstrating that disruption of the central cir-
cadian clock promotes cancer development and progression in rodents.

3.2. Variation in cancer phenotypes reported for circadian
gene-mutant mouse models
The role of mammalian circadian genes in cancer genetics was first reported
in 2002 in a study showing that mice expressing a mutant PER2 ( Per2 m/m )
defective in PER2-mediated protein/protein interactions due to an
85-amino acid in-frame deletion in the PAS domain of Per2 gene display
multiple tumor-prone phenotypes including increased spontaneous and
g -radiation-induced lymphoma, hyperplastic growth in salivary and prepu-
tial glands, resistance to radiation-induced apoptosis in thymocytes, and
deregulation of key tumor suppressors, cyclins, and proto-oncogenes, such
as p53 , Gadd45a , Cyclin D1 , Cyclin A , c-Myc , and Mdm2 . 123,124 The same

study also shows that Per2 -null ( Per2 / ) mice display similar cancer-prone
phenotypes as Per2 m/m mice (Supplemental data). 124
In contrast, other reports indicate that mice deficient in other core circa-
dian genes either lack neoplastic phenotypes or are tumor resistant. For exam-
ple, mice lacking Bmal1 ( Bmal1 / ) show a significantly reduced life span and
premature aging, but not spontaneous tumor development. 125 Hepatocytes in
mice lacking both Cry1 and Cry2 ( Cry1 / ; Cry2 / ) proliferated slower than
wild-type (Wt) hepatocytes in the first 72 h immediately after partial hepatec-
tomy. 126 Ablation of both Cry1 and Cry2 reduced cancer risk for p53- null
mice. 127 Clock -mutant ( Clock m/m )and Cry1 / ; Cry2 / mice did not show

predisposition to cancer in response to a low dose of g -irradiation. 128,129 Fur-
thermore, MEFs isolated from Cry1 / ; Cry2 / mice do not

show