Humans are synchronized to the 24-hour day by the light-dark cycle of the environment. Through alteration of the suprachiasmatic nucleus (SCN), the brain’s circadian pacemaker, exposure to light at night (LAN) influences the functions in the body that operate with circadian regularity, including the endocrine, immune and digestive systems. The SCN also signals to the pineal gland to modulate production of melatonin, a hormone that has established antimitotic and antiproliferative properties, and has been shown to regulate estrogen and other hormones important in breast cancer etiology.
People who work occupational night shifts are exposed to LAN and thereby experience circadian disruption, including delayed melatonin onset and reduction in peak nightly production. In 2007, the International Agency for Research on Cancer (IARC) at the World Health Organization (WHO) declared shift work that involves circadian disruption to be “probably carcinogenic to humans” (group 2A). The IARC working group cited strong experimental evidence from animals and supportive but limited human evidence from epidemiologic studies.
This dissertation investigates several relationships on the pathway from rotating night shift work exposure to breast cancer, through mammographic breast density. Mammographic density, or the proportion of fibroglandular tissue in a woman’s breast as viewed on a mammogram, is the strongest risk factor for breast cancer, and has been reported as associated with a 4-6 fold increased risk of breast cancer. It is therefore, a reasonable intermediate endpoint for breast cancer.
The analyses in this dissertation use data from two large longitudinal cohorts of female registered nurses in the United States, the Nurse’s Health Study and Nurse’s Health Study II, and are presented in a series of three papers. In the first paper, the prospective and long-term association of rotating night shift work and breast cancer is assessed with 24 years of follow-up, allowing for some analysis of the timing of exposure and tumor subtypes. In the second paper, the prospective relationship of rotating night shift work and mammographic density, as measured from screening mammograms, is evaluated. In the third paper, first morning void urinary 6-sulfatoxymelatonin, the main metabolite of melatonin excreted in urine, serves as a biomarker of circadian disruption, and is evaluated in relation to mammographic density in a cross-sectional analysis.
Overall, this dissertation work provides evidence in favor of an association between long-term rotating night shift work and breast cancer, and suggests that long durations of shift work early in a nurse’s career may be of particular importance. Such shift work may occur in a time period, between puberty and breast involution due to childbirth or aging, during which breast tissue is vulnerable to carcinogenic influences. Rotating night shift work and a single measure of urinary melatonin did not appear to be related to mammographic breast density, suggesting that if rotating night shift work raises a woman’s risk of breast cancer, it is unlikely to do so through influence on mammographic density
