Pillow Talk: The Possible Link Between Circadian Disruption and Breast Cancer Metastasis

While insufficient sleep has been shown to have a litany of adverse endocrine effects, a new study presented at ENDO 2019 revealed the possible dangers of dim light exposure at night that could cause breast cancer to metastasize to the bones.

In 2019, sleep is becoming a precious commodity. The Centers for Disease Control and Prevention report that more than a third of adults in the U.S. get less than the recommended amount of sleep per night, while a study by the RAND Corporation concludes that this lack of sleep costs the U.S. $411 billion a year.

But it’s not just the money lost to productivity that’s the problem. Both the CDC and the RAND Corporation declared lack of sleep a public health concern, and both organizations have offered recommendations for improving sleep: set consistent sleep times, exercise, limit the use of electronic devices before bedtime, and so on. Simple solutions, but not always easy ones.

Indeed, insufficient sleep has well documented adverse health effects. And endocrinologists are discovering and documenting even more of these effects. A 2015 Journal of Clinical Endocrinology & Metabolism article showed that even one night of wakefulness can lead to alterations in epigenetic and transcriptional profile of core circadian clock genes in key metabolic tissues. And now, a new study presented at ENDO 2019 in New Orleans further reveals endocrinology’s role in sleep health.

Muralidharan Anbalagan, PhD, an assistant professor at the Tulane University School of Medicine in New Orleans, La., at ENDO showed for the first time in a mouse study that exposure to dim light at night – no more than the light sneaking in under a door – may contribute to the spread of breast cancer to the bones, a growing problem in a society where smart phones twinkle throughout the night and streetlights bathe people’s windows in that warm yellow glow.

Night Shift

In 2014, Anbalagan and his team published a paper in Cancer Research titled “Circadian and melatonin disruption by exposure to light at night drives intrinsic resistance to tamoxifen therapy in breast cancer.” In that article, the authors pointed out that disruption of circadian rhythms from night shift work or disturbed sleep-wake cycles may lead to an increased risk of breast cancer and that light exposure at night suppresses the nocturnal production of melatonin that inhibits breast cancer growth. (The World Health Organization has designated night shift work involving light exposure as a “possible human carcinogen.”)

During that previous study, animals exposed to dim light at night showed increased tumor growth, and they developed a resistance to tamoxifen, a drug used to treat breast cancer. “Strikingly,” the authors concluded, “our results also showed that melatonin acted both as a tumor metabolic inhibitor and a circadian-regulated kinase inhibitor to reestablish the sensitivity of breast tumors to tamoxifen and tumor regression. Together, our findings show how [dim light exposure at night]-mediated disturbances in nocturnal melatonin production can render tumors insensitive to tamoxifen.”

“If you don’t adjust your lifestyle, the circadian disruption by light at night is going to be a huge problem, especially for people who live in large, bright cities as well exposure of lights to night shift workers such as nurses and flight attendants.” – Muralidharan Anbalagan, PhD, assistant professor, Tulane University School of Medicine, New Orleans, Louisiana

More than 150,000 U.S. women had breast cancer in 2017 that metastasized, according to an estimate from the National Cancer Institute. When breast cancer spreads, it often goes to the bones, where it can cause severe pain and fragile bones.

“Since breast cancer metastasizes to bone and melatonin has a bone protecting effect, I planned to do this [current] study,” Anbalagan says. He presented his team’s findings from the current study, “Disruption of the Circadian Melatonin Signal by Dim Light at Night Promotes Bone-lytic Breast Cancer Metastases,” last month in New Orleans.

In this preliminary study funded by the Louisiana Clinical and Translational Science Center (LACATS) in collaboration with Louisiana Cancer Research Consortium (LCRC) & Tulane Center for Circadian Biology, the researchers created a mouse model of bone metastatic breast cancer. They injected estrogen receptor-positive human breast cancer cells that have a low propensity to grow in bones into the tibia of female mice. Like humans, the mice used in this study produce a strong nighttime circadian melatonin signal. All mice were kept in the light for 12 hours each day. One group of three mice was in the dark the other 12 hours, which helped them produce high levels of endogenous melatonin. Another group spent 12 hours in light followed by 12 hours in dim light at night, which suppressed their nocturnal melatonin production.

X-ray images showed that mice exposed to a light/dim light cycle had much larger tumors and increased bone damage compared with mice kept in a standard light/dark cycle, he reported. “Our research identified the importance of an intact nocturnal circadian melatonin anti-cancer signal in suppressing bone-metastatic breast tumor growth,” Anbalagan says.

Too Plugged In?

There are dozens of factors that contribute to sleep loss in this modern, fast-paced society: caffeine use, alcohol use, stress, screen time, shift work. But while this new research indicated nighttime dim light exposure in the promotion of breast cancer metastases, the study also revealed some a possible and promising therapeutic target for treating breast cancer and preventing its spread to the bones. The researchers write in their ENDO 2019 presentation abstract that patients treated with metastatic breast cancer are treated with doxorubicin (Dox), a form of chemotherapy which itself can promote bone damage. “Multiple studies demonstrate adverse/toxic effects of Dox on bone including suppressed osteoblast differentiation and decreased bone volume,” Anbalagan says. “Children treated with Dox are reported to suffer bone damage leading to increased fracture risk. These adverse effects heighten the concern for patients receiving Dox as a part of their therapy.”

However, the researchers found that by using Dox in circadian alignment with melatonin in the mice, they saw reduced tumor growth in bone, reduced bone erosion, and promotion of formation of new bone. “Successful use of this chronotherapeutic use of Dox and [melatonin] in clinical trials increasing efficacy in preventing or suppressing breast cancer metastasis to bone while decreasing toxic side effects of doxorubicin would provide a revolutionary advancement in the treatment of bone metastatic breast cancer and decrease the morbidity and mortality associated with breast cancer metastasis to bone,” the authors write.

“Circadian disruption by light at night is not only a risk factor in cancer, but also in metabolic diseases like diabetes.” – Muralidharan Anbalagan, PhD, assistant professor, Tulane University School of Medicine, New Orleans, Louisiana

And while melatonin can be bought over the counter, Anbalagan says that natural melatonin is better. Still, he recognizes that can’t always be the case. “It’s is always better to have natural melatonin signaling through sleeping in dark, but most of the time it is not realistic,” he says. “So it is better to take a melatonin supplement to restore the circadian rhythm.”

Anbalagan says the next steps for his team will be expanding this study and exploring the mechanisms to reveal the key players involved in promoting breast cancer and the involvement of melatonin receptors. For now, it’s just a matter of recognizing that the circadian system is extremely important for overall health. “Circadian disruption by light at night is not only a risk factor in cancer, but also in metabolic diseases like diabetes,” he says.

“I think in today’s plugged-in world, it is really a huge problem,” Anbalagan continues. “If you don’t adjust your lifestyle, the circadian disruption by light at night is going to be a huge problem, especially for people who live in large, bright cities as well exposure of lights to night shift workers such as nurses and flight attendants.”

-Bagley is the senior editor of Endocrine News. He wrote about the impacts of some endocrine treatments on addictive behaviors in the March issue.

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