Table 1.
Roles of clock genes in breast cancer development.
| Circadian genes | Experimental approaches | Phenotype | Possible mechanism | Reference |
|---|---|---|---|---|
| CLOCK | Immunohistochemical assay(s) and qRT-PCR | Overexpressed in breast cancer cells; low expression in healthy breast tissue | Increased methylation in CLOCK promoter decreases breast cancer risk | (77, 78) |
| Knockdown(s) | Reduced cell proliferation; downregulation of cancer-associated genes (CCL5, BDKRB2, and SP100) | E2–estrogen receptor (ER) pathway may couple to the circadian machinery due to presence of estrogen response element in the CLOCK promoter | (77, 78) | |
| BMAL1 | qRT-PCR | Disrupted mRNA expressions in breast cancer cells | Not clear | (67, 80–83) |
| Knockdown(s) | Promoted cancer cell proliferation and invasion in vitro and tumor growth in vivo | Antagonized Bcl-w oncogene, which can activate phosphoinositide 3-kinase (PI3K)/Akt/MMP2 pathway; effects on p53 and c-myc are cell-type specific | (71, 79) | |
| PER1, 2, and 3 | Immunohistochemical assay(s) and qRT-PCR | Downregulated in ER-positive breast cancer cells | Methylation in PER promoter in ER+/PR+ breast cancer tissues | (70, 75, 76) |
| Knockdown(s) | Aberrant circadian oscillation of other clock genes; enhanced tumor growth in vivo; changed the structure of breast acinus | Coupling with E2–ER pathway and p53 pathway | (66) | |
| Overexpression | Significantly inhibited cell growth and promoted apoptosis | Inhibit the activation of ER and p53 target genes | (64, 72) | |
| CRY1 and 2 | qRT-PCR | Disrupted mRNA expressions in breast cancer cells | Not clear | (67, 80) |
| REV-ERBα | RNAi screen | Co-expression in ERBB2-positive breast tumors (HER2+ subtype) | Upregulating several genes that are involved in de novo fatty acid synthesis, which further enhance the energy production for survival | (86) |
| REV-ERBβ | Overexpression | Protect tumor cells against chemotherapy | Not clear | (84) |