Circadian clocks and breast cancer

Breast Cancer Research

Table 1 Genetic associations between circadian clocks and breast cancer

Mutation/SNP	Possible mechanism	Phenotype
CLOCK		Self-renewal capacity of mammary progenitor cells becomes compromised (our unpublished data)
Hypermethylation of Clock promoter	Mediates CCL5 expression	Reduced breast cancer risk [36]
NPAS2 Ala394Thr SNP	Altered NPAS2 protein structure	Increased breast cancer risk [55]
Per1 deficient	Alters expression of checkpoint proteins ATM and Chk2	Increased proliferation [41]
Per1 overexpression	Impairs p53 leading to decreased apoptosis, deregulation of c-myc/CyclinD1/Gadd45	Reduces proliferation in colon, lung and breast cancer cell lines [41]
Per2 deficient	Increases OCT1 binding to EMT genes Slug, Snail and Twist1	Higher tumour incidence, increased susceptibility to radiation-induced malignant lymphoma [39]
Per2 overexpression	Cell cycle arrest, growth inhibition, apoptosis induction	Suppresses breast cancer in vivo [40, 41]
Per3 deficient		Higher probability of cancer recurrence [7, 62]
Cry deficient	Disrupted cell cycle regulation via de-regulation of Wee-1 and CyclinD1
BMAL1/Era/Per2 KO	Prevents mammary acinar formation	Facilitates invasion and metastasis [56]
BMAL1 overexpression	Binds to p53 promoter	Tumour suppression [61]

Circadian mutations covered in this review and their links to cancer. Both epidemiological and experimental data are included, along with possible mechanisms and resultant phenotypes, where known
KO knockout, SNP single nucleotide polymorphism

ISSN: 1465-542X