Table 2.

Epidemiological evidence linking circadian disruption and breast cancer. Exposure to light at night, either (a) without or (b) with consideration of genotype.

a. Human Breast Cancer Association Studies
Study	Type	Exposure	Conclusion
Circadian disrupting exposures and breast cancer risk: a meta-analysis [75]	Meta-analysis	Shift work, short sleep duration, employment as flight attendant	Circadian disruption is associated with an increased breast cancer risk in women. (RR = 1.14; 95% CI 1.08–1.21).
Rotating Night-Shift Work and the Risk of Breast Cancer in the Nurses’ Health Studies [76]	Two prospective cohort studies (NHS I and II)	Night shift work	Long term night shift work had a higher risk of breast cancer. Pronounced with shift work during young adulthood. (HR = 2.15, 95% CI: 1.23, 3.73
Night-shift work and breast and prostate cancer risk: updating the evidence from epidemiological studies. Night-shift work and breast and prostate cancer risk: updating the evidence from epidemiological studies [77]	Meta-analysis	Night shift work	Risk is inconclusive and more studies are required
Evaluating the Association between Artificial Light-at-Night Exposure and Breast and Prostate Cancer Risk in Spain (MCC-Spain Study) [78]	Population based multi case-control study	Artificial light at night	Prostate and breast cancer were associated with high estimated exposure to outdoor light at night
Night Shift Work and Risk of Breast Cancer in Women [79]	Case-control	Night shift work	Positively associated night shift work with breast cancer. (OR = 8.58; 95% CI: 2.19–33.8)
Outdoor light at night at residences and breast cancer risk in Canada [80]	Population based case-control study	Outdoor light at night	Outdoor light at night has a small effect or no effect on breast cancer risk
NTP Cancer Hazard Assessment Report on Night Shift Work and Light at Night [81]	Systematic review	Night shift work, light at night	Likely causal relationship of persistent night shift work, particularly in young adults, to developing breast cancer
b. Studies Including Genetic Variants
Study	Type	Exposure	Outcome
Period3 structural variation: a circadian biomarker associated with breast cancer in young women [82]	Case-control study	PER3 variation	Increased risk of breast cancer in premenopausal women
Circadian genes and breast cancer susceptibility in rotating shift workers [83]	Prospective cohort	Shift work	Common variation in circadian genes play at most a small role in breast cancer risk among women of European ancestry. Neuronal PAS domain protein 2 (NPAS2) was strongly associated with breast cancer risk (p-value = 0.0005)
Breast cancer risk, night work, and circadian clock gene polymorphisms [84]	Population-based case-control study in France	Night shift work	Circadian clock gene variants modulate breast cancer risk. SNPs in RORA (rs1482057 and rs12914272) and in CLOCK were associated with breast cancer risk.
Circadian gene variants and breast cancer [85]	Epidemiological studies cited	Light at night	Circadian gene variants are significantly associated with breast cancer risk. BMAL1, BMAL2, CLOCK, NPAS2, CRY1, CRY2, PER1, PER3 and TIMELESS.
BRCA1 and BRCA2 Gene Expression: Diurnal Variability and Influence of Shift Work [86]	Cohort study	Night shift work	Lower BRCA1 and BRCA2 expression were found in a group of shift workers. It may be one of the potential factors related to the higher risk of breast cancer.