RESUMO
Evidence is mounting that circadian disruption (CD) is a potential carcinogen in breast cancer development. However, despite the growing concern, to our knowledge, no studies have attempted a genome-wide analysis of CD-induced gene expression changes in mammary tissues. Using a rodent model system, a proven photoperiod-shifting paradigm, varying degrees of CD, and Illumina sequencing, we performed an exploratory genome-wide mRNA analysis in mammary tissues. Even though our analysis did not identify any significant patterns in mRNA levels based on the degree of CD, and the majority of groups did not show changes in gene expression on a large-scale, one group (two-week chronic ZT19) displayed 196 differentially expressed genes, 51 of which have been linked to breast cancer. Through gene-specific pathway analysis, the data illustrate that CD may promote breast cancer development through downregulation of DNA repair and p53 signaling pathways, thus promoting genomic instability and cancer development. Although these results have to be interpreted with caution because only a single group illustrated drastic changes in transcript levels, they indicate that chronic CD may directly induce changes in gene expression on a large-scale with potentially malignant consequences.
RESUMO
Breast cancer is already the most common malignancy affecting women worldwide, and evidence is mounting that breast cancer induced by circadian disruption (CD) is a warranted concern. Numerous studies have investigated various aspects of the circadian clock in relation to breast cancer, and evidence from these studies indicates that melatonin and the core clock genes can play a crucial role in breast cancer development. Even though epigenetics has been increasingly recognized as a key player in the etiology of breast cancer and linked to circadian rhythms, and there is evidence of overlap between epigenetic deregulation and breast cancer induced by circadian disruption, only a handful of studies have directly investigated the role of epigenetics in CD-induced breast cancer. This review explores the circadian clock and breast cancer, and the growing role of epigenetics in breast cancer development and circadian rhythms. We also summarize the current knowledge and next steps for the investigation of the epigenetic link in CD-induced breast cancer.
Assuntos
Neoplasias da Mama/genética , Proteínas CLOCK/genética , Relógios Circadianos/genética , Epigênese Genética/genética , Animais , Feminino , HumanosRESUMO
Breast cancer is the most common malignancy affecting women worldwide, and evidence is mounting that circadian-disruption-induced breast cancer is a warranted concern. Although studies on the role of epigenetics have provided valuable insights, and although epigenetics has been increasingly recognized in the etiology of breast cancer, relatively few studies have investigated the epigenetic link between circadian disruption (CD) and breast cancer. Using a proven photoperiod-shifting paradigm, differing degrees of CD, various tissue-extraction time points, and Illumina sequencing, we investigated the effect of CD on miRNA expression in the mammary tissues of a rodent model system. To our knowledge, our results are the first to illustrate CD-induced changes in miRNA expressions in mammary tissues. Furthermore, it is likely that these miRNA expression changes exhibit varying time frames of plasticity linked to both the degree of CD and length of reentrainment, and that the expression changes are influenced by the light and dark phases of the 24-hour circadian cycle. Of the differentially expressed miRNAs identified in the present study, all but one have been linked to breast cancer, and many have predicted circadian-relevant targets that play a role in breast cancer development. Based on the analysis of protein levels in the same tissues, we also propose that the initiation and development of CD-induced breast cancer may be linked to an interconnected web of increased NF-κB activity and increased levels of Tudor-SN, STAT3, and BCL6, with aberrant CD-induced downregulation of miR-127 and miR-146b potentially contributing to this dynamic. This study provides direct evidence that CD induces changes in miRNA levels in mammary tissues with potentially malignant consequences, thus indicating that the role of miRNAs in CD-induced breast cancer should not be dismissed.