Aberrant methylation of miR-34b is associated with long-term shiftwork: a potential mechanism for increased breast cancer susceptibility.
OBJECTIVE
Although the evidence linking exposure to light at night (LAN) and breast cancer risk continues to accumulate, the molecular mechanisms driving this association remain to be fully elucidated. We have previously suggested that long-term exposure to LAN through shiftwork may result in dysregulated patterns of methylation genome-wide. In this study, we investigate the link between miR-34b, a miRNA suggested to be an important tumor suppressor, and shiftwork-related breast cancer.


METHODS
Methylation states in the miR-34b promoter region were previously compared between 10 female long-term shiftworkers and 10 folate intake- and age-matched female dayworkers participating in the Danish "Diet, Cancer and Health" prospective cohort study. In order to further explore the functional role of miR-34b in breast tumorigenesis, a genome-wide expression microarray was carried out in miR-34b-overexpressed MCF-7 breast cancer cells and the identified transcripts were further analyzed for network and functional interrelatedness using Ingenuity Pathway Analysis software.


RESULTS
We observed a 49.1 % increase in miR-34b promoter methylation among shiftworkers at a CpG site in this region (p = 0.016). Transfection of the miR-34b mimic in an MCF-7 breast cancer cell line induced differential expression of 230 transcripts that are involved in the interferon-mediated antiviral response as well as apoptotic and antiproliferative gene networks.


CONCLUSIONS
Together, our results suggest that long-term shiftwork may increase the risk of breast cancer via methylation-based suppression of miR-34b and a consequent reduction in immunomediated anti-tumor capacity and support our previous findings that LAN may induce epigenetic alteration of cancer-relevant microRNAs.
Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, 06520, USA.|Key Laboratory of Environmental Medicine Engineering, School of Public Health, Southeast University, Nanjing, 210009, China.
Ran
R
Liu
Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, 06520, USA.
Daniel I
DI
Jacobs
Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
Johnni
J
Hansen
Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, 06520, USA.
Alan
A
Fu
University of Connecticut Health Center, Farmington, 06030-6325, CT, USA.
Richard G
RG
Stevens
Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, 06520, USA. yong.zhu@yale.edu.
Yong
Y
Zhu
D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D015331:Cohort Studies; D019175:DNA Methylation; D004198:Disease Susceptibility; D057890:Epigenomics; D005260:Female; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D008027:Light; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D008875:Middle Aged; D009784:Occupational Diseases / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D011795:Surveys and Questionnaires; D014940:Work Schedule Tolerance
C522425:MIRN34 microRNA, human; D035683:MicroRNAs