Circadian Rhythm Gene Plays a Role in Breast Cancer Susceptibility

Frank Han | frank.han@yale.edu October 1, 2010

Groundbreaking research at the Yale School of Public Health has shown that changes in a gene responsible for regulating the body’s circadian rhythm increase the risk of breast cancer in women. Published recently in the journal Cancer Research, this study was conducted by Dr. Yong Zhu, an associate professor at the Yale School of Public Health. By studying blood samples from a case-control study of breast cancer as well as the MCF7 breast cancer cell line, Zhu and his lab were able to show that both genetic and epigenetic changes in the CLOCK gene, one of the nine core genes that control our circadian rhythm, can serve as susceptibility biomarkers for breast cancer.

The circadian rhythm is the biological “clock” that governs every living organism, including humans. Because it is adapted to the Earth’s rotation, the circadian rhythm is roughly a 24-hour cycle in which the 12 hours of the night correspond to our regular sleeping pattern. However, “artificial light in the last 150 years has disrupted many people’s natural circadian rhythm,” said Zhu. “People now are staying up much later than before because of artificial light.”

Previous studies had already shown that animal models exposed to extended periods of artificial light have impaired motor skills. More significantly, in the past eight years, night shift workers have been found to have higher risks for breast, colon, and prostate cancers. What was unique about the Yale group’s research, however, was that they took a molecular approach to cancer epidemiology. As Zhu explained, “We are actually using human samples to detect new circadian biomarkers that can predict diagnosis, progression, and survival rate of cancers.”

To test the hypothesis that the genetic and epigenetic changes in the CLOCK gene are different in cancer patients in comparison to cancer-free individuals, Zhu’s group screened the blood samples of a group of breast cancer patients and a control group. They discovered distinct epigenetic changes in addition to different mutation frequencies. Epigenetic changes, such as promoter methylation, can influence gene regulation but do not directly alter the DNA code. There was a significantly lower level of methylation of the promoter region on the CLOCK gene in breast cancer patients compared to the cancer-free controls. Thus, because methylated DNA leads to decreased gene expression, the lower level of methylation in breast cancer tissue results in an overexpression of the CLOCK gene. In addition, this result confirmed findings that showed greater expression of the CLOCK gene in breast tumor tissues.

Using siRNA techniques and whole genome expression array analysis, Zhu’s group was also able to link 154 other genes that were affected by the knockdown of the CLOCK gene to cancer susceptibility. Some of these genes have been linked by research databases to be not only cancer-related but also specific for breast cancer. In fact, six out of the nine circadian rhythm genes, including CLOCK, have already been linked to breast cancer from Zhu’s previous studies. In the future, Zhu plans to use these genes in combination as an accurate prognostic biomarker for breast cancer.

Extra Readings:

Hansen J. Increased breast cancer risk among women who work predominantly at night. Epidemiology. 2001; 12:74–7.

Hoffman, A.E., et al. (2010). CLOCK in Breast Tumorigenesis: Genetics, Epigenetic, and Transcriptional Profiling Analyses. Cancer Research. February 15, 2010.

Stevens RG. Electric power use and breast cancer: a hypothesis. Am J Epidemiol 1987;125:556–61.

Stevens RG. Circadian disruption and breast cancer: from melatonin to clock genes. Epidemiology 2005;16:254–8.

http://publichealth.yale.edu/faculty/zhu.html