Our data indicate that deletion and/or reduced expression of the PER3
gene on human chromosome 1p36 is associated with breast cancer recurrence, particularly in patients with ER-positive tumors treated with tamoxifen who did not receive chemotherapy. No effect of deletion was seen in patients with basal type ER-negative breast tumors. Within the ER-positive category, the effect was primarily in tumors classified as luminal A–type or ERBB2-type, but not in the luminal B–type, which shares some expression features with basal tumors.36,37
Direct evidence for a causal role for loss of PER3
, rather than an alternative gene in this commonly deleted region of the genome,5,6
comes from analysis of two different mouse models of breast cancer. Both chemically induced and Neu (ErbB2
) –induced breast cancers are increased in frequency and/or reduced in latency in mice carrying inactivated Per3
alleles. Although these data do not prove that Per3
is the only functional tumor suppressor gene in this chromosome interval, they indicate that Per3
is a bona fide tumor suppressor in these mouse models, with a key role in breast tissue.
While disruption of the mouse period gene family members Per1
by gene targeting induces biologic clock phenotypes,39
loss of Per3
function induces only subtle effects on circadian rhythm.13,40
Nevertheless, evidence in favor of PER3
involvement in both sleep disruption and breast cancer comes from studies of a human structural polymorphism in the PER3
coding sequence that has been associated with delayed sleep phase syndrome, diurnal preference, and waking performance,31,41,42
but also with increased breast cancer risk,19
particularly in premenopausal women.
Although the specific molecular mechanisms remain to be elucidated, increasing evidence points to a role for circadian rhythm genes in cell cycle control and DNA damage responses11,43
as well as in hormonal control of gene expression.17,18 PER2
has been identified as an estrogen-inducible ER corepressor that forms heterodimers with PER3
to enter the nucleus. Deletion of PER3
prevents nuclear import and, instead, promotes accumulation of PER2
in the cytoplasm.44
Whether coordinated functional deregulation of all period family genes occurs in breast cancers remains to be determined.
There are several clinical implications of these observations. First, the presence of PER3
deletions in ER-positive tumors may identify patients who do not respond to tamoxifen-based hormone therapy and who may benefit from other therapeutic regimens. Second, previous data from clinical trials of chronotherapy suggest that the timing of cancer treatment during the day may affect individual patient responses.45,46
Elucidation of the relationship between control of sleep homeostasis and circadian rhythms, PER
gene expression, and DNA damage responses may help in understanding the epidemiologic data linking sleep disruption to breast cancer susceptibility,17,20,21
but further detailed studies will be required to elucidate the exact mechanisms involved. Finally, small-molecule drugs that help to restore the balance of the biologic clock in individuals with frequent sleep disruption may have potential as chemopreventive agents for breast and some other cancer types.