Deletion of the PER3 gene on chromosome 1p36 in recurrent ER-positive breast cancer.
OBJECTIVE
To investigate the role of the PER3 circadian rhythm gene, located within the commonly deleted region of chromosome 1p36, in human breast cancer development.


METHODS
The frequency of genetic alterations at 1p36 and PER3 gene copy number status were analyzed in 180 lymph node-negative breast cancers from patients who had received treatment with chemotherapy and/or tamoxifen. The expression levels of PER3 were also analyzed using published microarray profiles from > 400 breast cancer samples. Finally, the effect of loss of Per3 on tumor susceptibility was tested using two mouse models of breast cancer.


RESULTS
Deletion of PER3 is directly related to tumor recurrence in patients with estrogen receptor (ER) - positive breast cancers treated with tamoxifen. Low expression of PER3 mRNA is associated with poor prognosis, particularly in a subset of tumors that are ER positive, and either luminal A or ERBB2-positive tumors. Mice deficient in Per3 showed increased susceptibility to breast cancer induced by carcinogen treatment or by overexpression of Erbb2.


CONCLUSIONS
Disruption of PER3 function may serve as an indicator of probability of tumor recurrence in patients with ER-positive tumors. Further investigations of this pathway may reveal links between deregulation of sleep homeostasis and breast tumorigenesis.
Climent
Joan
J
Helen Diller Family Comprehensive Cancer Center, Cancer Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
Perez-Losada
Jesus
J
Quigley
David A
DA
Kim
Il-Jin
IJ
Delrosario
Reyno
R
Jen
Kuang-Yu
KY
Bosch
Ana
A
Lluch
Ana
A
Mao
Jian-Hua
JH
Balmain
Allan
A
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D009364:Neoplasm Recurrence, Local; D056950:Period Circadian Proteins / Q000235:genetics*; D011379:Prognosis; D011960:Receptors, Estrogen; D017384:Sequence Deletion; D016019:Survival Analysis
C512644:PER3 protein, human; D056950:Period Circadian Proteins; D011960:Receptors, Estrogen