How the circadian clock may affect cancer

When it came to advice, Dr. Ann Hsing’s grandmother kept it simple: Eat well. Exercise. Go to bed early.

Hsing, chief scientific officer for the Cancer Prevention Institute of California, did her best on the first two. But sleep, when her research was so pressing?

 “I used to tell her, ‘No, I can’t go to bed early—I have to figure out how circadian rhythms affect cancer risk,’” Hsing told an audience at a Fred Hutchinson Cancer Research Center symposium on cancer and the circadian clock.

Conceding that “she may be right,” Hsing dedicated her talk at Monday’s symposium to her grandmother, who died in her sleep last year at age 100, “extremely healthy to the last second.”

The symposium, sponsored by the Hutch’s Public Health Sciences Division, brought Hsing and five other top circadian clock researchers together to examine the current state of the science in the hope that in the near future, sleep—or some other adjustment—can be added to the list of cancer prevention recommendations.

The circadian clock is the body’s molecular clock, a natural, roughly 24-hour cycle that regulates sleep, metabolism, the immune system, temperature, renal function, gene activity and other physiological and biochemical processes. Circadian rhythms occur in all the body’s organs, tissues, and cells and are synchronized by a central pacemaker in the brain’s hypothalamus.

There is considerable evidence that shift work, jet lag, light at night, or other disruptions to the circadian clock can lead to cardiovascular disease, obesity, diabetes, hypertension, depression and other health problems. In 2007, the International Agency for Research on Cancer classified shift work resulting in circadian disruption as a probable human carcinogen. 

The melatonin hypothesis

The Hutch’s Dr. Scott Davis in 2001 published one of the first studies to show an increased risk of breast cancer in nurses working night shifts. Future research is needed to understand the risks for other cancers and to address individual susceptibility, he said Monday.

“With a better understanding of the biological basis for the detrimental effects of night shift work, it should be possible to design preventive interventions to reduce the relevant exposure or exposures,” Davis said.

He and other researchers at first speculated that night shift work could raise breast cancer risk by increasing levels of circulating estrogen. But what they found instead was a decrease in circulating melatonin levels in night shift workers compared to day shift workers. Melatonin is a powerful hormone that is normally produced at night, but is suppressed by ambient light.

But the relationship between melatonin and cancer risk is not straightforward, researchers said. Several different variables are at play, including exposure to light at night, disrupted or inefficient sleep and the influence of circadian genes.

Complicating factors

“Melatonin production surges at bedtime, peaks around 2 a.m., and drops sharply around 7 a.m.,” said Dr. Parveen Bhatti, assistant member of the Hutch’s Epidemiology Department in PHS. “It’s the timing and size of that peak that matters.”

Factors such as race may affect melatonin production. After a Shanghai study found no association between shift work and breast cancer, Bhatti and Davis compared Caucasian and Asian shift workers in Washington state and found that Asian women who worked night shifts were able to maintain higher levels of melatonin production than Caucasians on night shifts.

Another possible influence is chronotype—whether a person is naturally an early bird, a night owl, both or neither. Although night owls report higher job satisfaction on the night shift than morning people do, a study by Bhatti and Davis found that early birds maintained higher melatonin levels during night shifts than night owls, albeit lower than those working day shifts.

A night owl by nature, Hsing said she is trying to change her sleep habits (and take her grandmother’s advice) by making sure she goes to bed by 11 p.m. She gets up around 6 a.m. to 7 a.m.

“My own personal view, it’s not sleep duration alone—it is sleep efficiency,” she said. “And this is from my grandmother again: it is the time you go to sleep. Between 11 p.m. and 4 a.m. is the most critical time, when your blood is going through your liver and your body is doing repair. That’s from Chinese medicine.”

The circadian clock and skin cancer

Timing is also a factor in what symposium participants described as groundbreaking research on the circadian clock’s influence on skin cancer by Dr. Shobhan Gaddameedhi, a postdoctoral research associate at the University of North Carolina Lineberger Comprehensive Cancer Center who has just accepted a faculty position at Washington State University.

Skin cancer is the most common cancer in the United States. The main cause is DNA damage induced by the UV rays from sunlight. A mechanism called nucleotide excision repair is able to fix some of this damage at the cellular level and prevent it from developing into cancer.

Gaddameedhi’s research in mouse models has found that the circadian clock regulates the repair system’s activity. In his experiment, he irradiated mice with UV rays three times a week for 25 weeks. One group was irradiated at 4 a.m., the other group at 4 p.m. The morning group was five times more likely to develop tumors than the afternoon group.

Gaddameedhi speculates that the results could be the opposite in humans, who are diurnal rather than nocturnal and so run on a different clock. The findings suggest that people may be more at risk of developing cancer if they are exposed to UV rays in the afternoon rather than morning

His research is now extending into whether the circadian clock also determines the best times to receive chemotherapy treatments for cancer.

The search for prevention

As more research is being done into the genes that control circadian rhythms, some people may be found to have genes that protect against detrimental effects.

Said Hsing, “If we can identify people who can’t adjust, then they can choose a profession that’s less disruptive. Like we have personalized medicine, we can have personalized occupational therapy.”

As for melatonin, researchers debated whether the time was ripe for a clinical trial. Although the melatonin supplements sales have soared in the last five years, some argued that better data is needed to show how melatonin relates to cancer risk.

“Melatonin has the ‘natural,’ homeopathic aura about it, but we don’t know how much melatonin is in the products you buy or how much to take,” said Dr. Nathanial Watson, co-director of the University of Washington Medicine Sleep Center. “Light exposure in the morning could be way more important than melatonin at night.”

If there was one agreement at the symposium, it was that sleep doesn’t get the respect it deserves.

“We live in a sleep-deprived society,” said Watson, who described commuting every morning from Bainbridge Island to Seattle and seeing “all these guys dressed to the nines, in their $200 shoes,” sleeping on the ferry.

“A third of us are sleeping less than 6 hours a night, 1½ hours less than we were 100 years ago. But human sleep needs haven’t changed in that time.”

 The takeaway?

 “Reprioritize sleep in your life,” said Watson. “Sleep is vital to life.”