The Cancer/Clock Connection
words by susan preston / photograph by pete byron
Helmut Zarbl, professor of toxicology at UMDNJ-Robert Wood Johnson Medical School, associate director for
public health science at The Cancer Institute of New Jersey, and director of the National Institute for Environmental Health Science (NIEHS) Center for Environmental Exposures and Disease at EOHSI
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oxicologist Helmut Zarbl is challenged by this cancer puzzle: Why are people whose jobs require them to work the night shift at significantly greater risk of developing cancer? And is there a chemoprevention strategy to protect them?
“Epidemiological studies have consistently shown that people who work at night have a significantly increased risk of breast and possibly prostate cancer,” Zarbl says. “But we don’t know why this is so or whether we can change that outcome.”
His research, which until now has been done with laboratory animals, has uncovered two pieces of the puzzle. One indicates that when the body’s natural circadian rhythm is disrupted, certain hormone signaling pathways are knocked out of balance, which can lead to the formation of breast and perhaps prostate tumors. The other shows that a dietary supplement containing the trace element selenium appears to reverse this effect.
To complete the puzzle, he is conducting his first clinical research trial involving humans. The three-year project, funded by a $600,000 grant from the V Foundation for Cancer Research, will be conducted in two parts. In the first study, the team will determine what conditions cause a disruption of circadian rhythm in shift workers and, when that happens, if it also causes a dramatic imbalance in estrogen receptor molecules. Twenty healthy volunteers (10 females, 10 males) whose jobs require shift work (nurses, interns, residents) will be recruited. The participants will donate blood while working on the day shift and at least a week after working on the
night shift.
In the second study, 100 individuals from a wider variety of occupations requiring shift work — police officers, firefighters, other hospital workers, flight crews, factory workers — will donate blood so that scientists can study if shift work has the same effect on these workers. If so, study participants will be asked to take a daily dose of methylselenocysteine (MSC), a non-toxic dietary supplement containing selenium, or a placebo, for 30 days. Their blood will be analyzed for biomarkers of disrupted circadian rhythm prior to taking the supplement and a month after they have completed the regimen.
His research into MCS as an effective chemopreventive agent is based on several studies that selenium appears to prevent about 60 percent of mammary cancers in rats exposed to a chemical carcinogen. “Although studies have shown its effectiveness, we didn’t really understand how MSC-mediated chemoprevention works at the molecular level.”
To define the mechanism of action, Zarbl and his team compared the pattern of genes expressed in mammary glands of control and carcinogen-exposed rats fed with either a standard or an MSC supplemented diet. This led to the unexpected finding that both carcinogen exposure and dietary selenium had profound effects on the biological clock (circadian rhythm) in cells of the mammary gland. “We found that exposure to the carcinogen disrupted normal circadian rhythm of cells in mammary tissue. More importantly, we found that a chemoprevention regimen of MSC restored a normal rhythm.” Circadian rhythm is important because it controls and coordinates many of the cells’ functions throughout the day. Zarbl’s team therefore asked if changes in circadian controlled functions in mammary cells could contribute to an increased risk of cancer. What they found was a dramatic effect of the MSC on the rhythmic expression of ER‚ a recently discovered member of the estrogen receptor gene family that may function as a tumor suppressor in mammary cells.
“Based on these findings and our research, the hypothesis for our clinical research study is that the increased risk of breast and prostate cancer in shift workers is mediated by disruption of circadian rhythm, which can lead to imbalances in estrogen receptor levels,” Zarbl says. “In this study, we will directly test this hypothesis in shift workers and assess clock genes and estrogen receptor genes as biomarkers of disrupted circadian rhythm.
“We will then use these biomarkers to assess the efficacy of a simple dietary supplement with MSC to ameliorate the negative effects of shift work on circadian rhythm and estrogen receptor gene expression and cycling. Positive results from these two studies will provide the basis for longitudinal intervention studies to investigate selenium chemoprevention in people at elevated risk of breast and prostate cancer because of shift work.”
The selenium studies could lead to a simple, effective and safe intervention that involves dietary modification or supplementation with naturally occurring amino acid at doses within the normal range of human intake, without any toxicity or known adverse effects, or the need for hormonal supplements such as melatonin.