Circadian-disruption-induced gene expression changes in rodent mammary tissues

Abstract

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.

Octopamine Rescues Endurance and Climbing Speed in Drosophila Clkout Mutants with Circadian Rhythm Disruption

“…Spargel has been shown to be important for the exercise response in both flies and mammals and its homolog is also a known modulator of clock gene expression in mammalian studies [49,50]. These results are consistent with other models of circadian disruption that have reduced expression of these exercise-related proteins [51,52]. This reduced exercise capacity, along with reduced levels of molecules required for an exercise response may explain why we, consistent with others [53], did not find that exercise could effectively rescue the effects of rhythm disruptions.…”

Circadian clocks and breast cancer

“…Some of these miRNAs are interconnected with the expression of proteins known to have roles in breast cancer, such as NFkB and Stat3. The levels of some transcripts that encode proteins involved with cancer are also altered in circadian-disrupted mice [ 80 ].…”

Mechanisms of Breast Cancer in Shift Workers: DNA Methylation in Five Core Circadian Genes in Nurses Working Night Shifts

“…Altered expression of the circadian genes has also been observed in breast cancer cells and breast tumor tissues 19 , 20 . Changes in the expression of circadian genes may be involved in increased breast cancer risk by altering the cell cycle and apoptosis, and by changing the cellular metabolism 21 . In addition to genetic polymorphisms and changes in gene expression patterns, epigenetic variations in the levels of 5-methyl cytosine (5mC) in circadian genes may affect breast cancer susceptibility in shift workers, as shift work may lead to differential methylation of these genes 22 - 24 .…”