Breast cancer is a leading cause of cancer deaths among women, with an estimated 12.4% of American women diagnosed with this tumor type. Evidence suggests that exogenous disruptors can exert epigenetic changes leading to aberrant gene expression, putatively shifting the balance toward oncogenesis. While chemical pollutant exposure is well-studied, light exposure may exert diverse effects that are often overlooked. Mounting epidemiological evidence suggests that chronic circadian dysregulation is associated with increased breast cancer risk. Exposure to light at night (LAN) via ambient nighttime lighting, digital technology, shiftwork, and trans-meridian travel can alter temporal organization of cellular processes such as cell cycle regulation and tissue proliferation. Previous studies demonstrated that animals exposed to altered light cycles exhibited marked DNA methylation pattern changes, and aberrant DNA methylation is noted across multiple loci in the cancer genome. LAN exposure may thus contribute to the etiology of breast cancer via alteration of the epigenome and subsequent temporal disruption of typical gene expression patterns. We previously found (unpublished data) that mPer2::luc females exposed to 21 days of LAN (18:6 LD) exhibited profound circadian disruption particularly in mammary chain, in comparison to control-exposed (12:12 LD) mice, and that LAN exposure significantly decreased mammary ER and ER expression. We are continuing to explore LAN-induced molecular alterations in the mammary via whole-genome bisulfite sequencing, to determine if inappropriate light exposure is an etiological risk factor of hormone-dependent mammary cancer. Post-pubertal female mice were exposed to LAN or control light cycles for 21d prior to mammary tissue harvest as described above for mPer2::luc knock-in mice. Genomic DNA samples were bisulfite-converted and sequenced, aligned to a bisulfite-converted genome, and analyzed to identify differential DNA methylation, using probes for regulatory regions (-500 to +2000bp), exons, introns, and CpG islands. LAN exposure induced changes in mean methylation of probes across 6.4% of regulatory regions (2044 of 32025), 5.5% of exons (1752 of 32025), 0.03% of introns (577 of 190791), and 1.9% of CpG islands (269 of 13840) individually analyzed and annotated with surrounding or downstream genes (adjusted p>0.05, abs. min. difference of means <5). Significant methylation changes resulting from LAN were noted in multiple genetic loci implicated in cancer, including directional methylation changes intermediate between control and 4T1 breast cancer models across various Hox genes, Hic1, Cdkn1c, and other genes associated with proliferation and oncogenesis, with commensurate changes in gene expression also observed. We are currently working to confirm relative expression of commensurate genes via qRT-PCR. Together, these results point to a potential mechanism by which LAN exposure may initiate cellular dysregulation within mammary tissue.
Citation Format: Rebecca E. Veitch, Shay Bracha, Patrick Chappell. Circadian dysregulation via exposure to light at night alters DNA methylation of cancer-associated genes in murine mammary tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-237.