Abstract
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.
Highlights
In 2007, the International Agency for Research on Cancer concluded “shiftwork that involves circadian disruption is probably carcinogenic to humans” [1]
We investigated the effect of varying degrees of circadian disruption (CD) on miRNA expression in the mammary tissues of Sprague Dawley rats
None of the ZT19 groups showed any changes in miRNA expression (Figure 4), whereas with the exception of the two-week acute group, all the ZT06 groups showed differences in miRNA expression compared to the respective control groups (Figures 2 and 3)
Summary
In 2007, the International Agency for Research on Cancer concluded “shiftwork that involves circadian disruption is probably carcinogenic to humans” [1]. 22 nts long, mature miRNAs associate with the RNA induced silencing complex (RISC) and target the 3` UTR region of target mRNAs, resulting in gene degradation or suppression, depending on the level of complementarity between the miRNA and its target [7]. In mammals, through this mechanism a single miRNA can target multiple genes and influence a broad range of cellular processes related to cancer [7]. Tumour promoters referred to as oncomiRs, or both depending on the degree of malignancy, miRNAs can influence the progression of cancer through various mechanisms such as cellular differentiation, proliferation, and apoptosis [6, 7]
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