Link Between Circadian Rhythm Gene and Breast Cancer Identified

New research suggests that long durations of night shift work may have negative health consequences for women by making them more susceptible to breast cancer.

Scientists at the Yale School of Public Health found that epigenetic and genetic changes to a gene responsible for regulating the body’s circadian rhythm—known as the CLOCK gene—increase a woman’s risk of developing breast cancer.

While previous studies have shown that repeated disruptions to the body’s circadian cycles—such as a job requiring nighttime work—may negatively affect cellular function and increase the risk of breast cancer by as much as 50 percent, the underlying biological mechanisms were poorly understood. The public health researchers discovered that changes to the CLOCK gene—a key component of the molecular circadian regulatory system that enhances the expression of various genes—appear to trigger breast cancer susceptibility.

“Ideally, we will be able to use genetic and epigenetic profiling to identify a subset of women who are particularly susceptibility to the harmful of effects of shift work, and we could recommend these women not engage in occupations involving night work,” said Yong Zhu, associate professor at the School of Public Health and the study’s principle investigator.

Zhu has long studied the link between cancer and circadian rhythms, the roughly 24-hour cycle that regulates the body’s most basic functions and processes, and believes that repeated interruptions to these natural rhythms could be a “very significant” factor in breast cancer as well as prostate cancer, non-Hodgkin’s lymphoma and other forms of the disease. However, based on data from the Nurse’s Health Cohort, these negative health effects take a long time to develop. It is believed that women, for instance, have to work at least 20 years of rotating or night shift work to increase their risk. Based on these findings, Denmark’s government now compensates women who develop breast cancer after 20 years of night work.

Epigenetic variations influence gene regulation but do not directly alter the DNA code. The researchers discovered significantly less methylation (a chemical process that often leads to decreased gene expression) in the promoter region (which facilitates gene transcription) in the CLOCK gene in breast cancer patients, compared to the same region in individuals who were cancer-free. The CLOCK gene is overexpressed in breast cancer tumor tissue, and there was an even greater effect in women with estrogen and progesterone receptor-negative tumors, which is a more aggressive form of breast cancer.

Future research will focus on whether the circadian genes play a role in breast cancer by influencing hormone regulation, or whether other cancer pathways are perhaps more relevant. Zhu also plans to look at environmental factors, such as exposure to light at night, and whether these exposures have the ability to induce epigenetic alterations, such as those observed in the CLOCK promoter. This would provide a specific mechanism by which environmental circadian disruption could influence breast cancer risk in women, he said.

Aaron Hoffman, a postdoctoral student in Zhu’s lab and the study’s lead author, said that epigenetic analyses of breast cancer patients is particularly challenging because standard treatments for breast cancer (such as radiotherapy and chemotherapy) can influence epigenetic profiles. As a result, when patients with breast cancer are compared to cancer-free controls, the observed differences could have been caused by effects of treatment. The group was able to identify a subset of women who had not yet undergone treatment, making their epigenetic association analysis possible.

Other authors involved in the research are Chun-Hui Yi, Tongzhang Zheng, Derek Leaderer, Yawei Zhang, Theodore R. Holford and Jennifer Paulson of the Yale School of Public Health; Richard G. Stevens of the University of Connecticut Health Center; and Johnni Hansen of the Danish Cancer Society. The study appears as an online article in the journal Cancer Research.