Usually when all else fails with a technical device, a "reset" button can be pressed, preventing a glitch from going any further. What if that could be done with threats to a person's health? Investigators from The Cancer Institute of New Jersey (CINJ) and the Environmental & Occupational Health Sciences Institute (EOHSI) which is jointly administered by UMDNJ-Robert Wood Johnson Medical School and Rutgers, The State University of New Jersey, have discovered that a form of a dietary trace element known as selenium can help reset a cell's "biological clock" when it is disrupted by a chemical cancer-causing agent (carcinogen). The findings ultimately may help prevent the development of breast cancer. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School.
Studies have shown that one's "biological clock" (circadian rhythm) - responsible for regulating such functions as blood pressure, appetite, immune function and more - plays a critical role in the growth of cells and how those cells react to environmental and internal stressors. A person's normal circadian rhythm can be interrupted by genetic manipulation, exposure to chemical carcinogens, and exposure to light at night for people who do shift work. Such interruption, the researchers say, could negatively impact how cells respond to and repair DNA damage. Epidemiological studies have repeatedly shown that working the night shift, for instance, is linked to an increased risk of endometriosis, breast cancer in women, and prostate cancer in men, prompting the International Agency for Cancer Research to classify shift work as a probable human carcinogen.
Separate studies have shown that the organic form of selenium known as methylselenocysteine (MSC), produced by plants, exhibits chemopreventive effects in the early stages of tumor development by slowing growth when exposed to a chemical carcinogen. Other studies done previously by CINJ's Associate Director for Public Health Science, Helmut Zarbl, PhD, ATS, and colleagues, were the first to suggest an association between circadian rhythm and cancer prevention.
The team's current research, published in today's online edition of Cancer Prevention Research extends those findings with a focus on nitrosomethylurea (NMU), a chemical carcinogen. Although human exposure to this agent is rare, as it is not produced in mass quantities and is only used in the laboratory setting, exposure to other chemicals with the same mode of action (DNA alkylation) is not. In this latest study, the team demonstrated on experimental models that a single dose of NMU significantly disrupted circadian rhythm in mammary cells, indicating that loss of circadian rhythm from something other than shift work may also contribute to cancer. Investigators also discovered that the biological clock was reset and restored when dietary MSC was given following exposure.
While all cells in the body have a biological clock, these clocks all need to be synchronized in order to coordinate the body's overall physiology. Synchronization normally occurs as a result of blood levels in the hormone melatonin, whose levels are controlled by the amount of light entering the eyes. Melatonin synchronizes cellular clocks by binding to a specific receptor on the surface of all cells. This is why people often take melatonin to decrease the amount of time required to get over jet lag. Another study (Fang et. al.) showed that exposure to NMU prevented melatonin receptors from being produced in mammary (breast) cells, thus making them resistant to melatonin levels in the blood. Dietary MSC restores the normal rhythmic expression of the cell surface melatonin receptor, allowing melatonin to reestablish a normal biological clock.
How, then, does restoration of circadian rhythm prevent breast cancer development? According to the authors, it appears that the biological clock also regulates daily changes in the levels of gene encoding estrogen receptors, especially the growth inhibitory beta subtype (ERβ), other growth related genes and proteins that repair DNA damage induced by both environmental agents and those internal to the body. By interrupting the production of these genes, chemical carcinogens and shift work affect normal control mechanisms and make cells more vulnerable to mutations caused by DNA damage. By restoring normal circadian rhythm, MSC can reverse these effects, at least in experimental models, thus blocking estrogen-generated promotion of cancer development in breast tissue.
"These findings are significant because they show how disruption of circadian rhythm can increase the risk of mammary cancer risk, and how a simple dietary supplement can reverse this effect, restore rhythm, and reduce cancer incidence, at least in experimental models. If MSC has the same effect in people, our results could have significant implications for alleviating the increased risk of breast and prostate cancers associated with shift work," noted Zarbl, who is a professor of toxicology at UMDNJ-Robert Wood Johnson Medical School and the director of the National Institute of Environmental Health Sciences (NIEHS) Center for Environmental Exposures and Disease at EOHSI.
Zarbl and colleagues are nearing completion on the first phase of a related study whose focus is on hospital workers. The aim is to determine whether shift work also disrupts the cell's response to estrogens and if this effect can be reversed by dietary MSC.
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