Disturbance of circadian gene expression in breast cancer.
To explore the mechanism of the disruption of circadian rhythm in breast cancer, we examined the expression of nine circadian genes in 53 newly diagnosed breast cancers by immunohistochemical staining, mutational analysis, and methylation analysis of the promoter of circadian genes. Our results showed that 37 of the 53 breast cancer tissues had hypermethylation on the promoters of PER1, PER2, CRY1, or BMAL1. Twenty-five out of 53 paired noncancerous (normal) tissues had methylation on the promoter of PER1 or CRY1. Our results indicated a higher frequency of concurrent methylation of PER1 and CRY1 promoters in cancerous and normal tissues. Promoter methylation of the PER1 correlates with c-erbB2 immunohistochemical reaction of > or = 2+ (p = 0.012) and has a strong inverse correlation with estrogen receptor positivity (p = 0.016). We further analyzed the patterns of circadian gene expression by immunohistochemical methods and found that homogeneous expression of PER2 or BMAL1 is significantly associated with lymph node metastasis and poor prognosis. PER2 heterogeneous expression correlates with <2+ c-erbB2 immunohistochemical reaction. Heterogeneous expression of CLOCK is associated significantly with 3-year survival. In conclusion, the expression pattern of circadian genes might be a biomarker for the prognosis of breast cancer.
Kuo
Shou-Jen
SJ
Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
Chen
Shou-Tung
ST
Yeh
Kun-Tu
KT
Hou
Ming-Feng
MF
Chang
Ya-Sian
YS
Hsu
Nicholas C
NC
Chang
Jan-Gowth
JG
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D056926:CLOCK Proteins; D002940:Circadian Rhythm / Q000235:genetics*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins; D011401:Promoter Regions, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C538960:BMAL1 protein, human; C421902:PER2 protein, human; C538943:CLOCK protein, human