Working the night shift, frequently flying across time zones or keeping an irregular sleep schedule does more than just leave us exhausted; it can fuel the risk of aggressive breast cancer. Exactly how and why this happens has remained a mystery, until now.
A new study from the Texas A&M University College of Arts and Sciences led by Dr. Tapasree Roy Sarkar sheds light on this elusive link, finding that circadian disruptions change the structure of mammary glands and weaken the immune system's defenses, all the while pointing toward a new way to counteract these effects.
"Cancer keeps time," Sarkar said. "If your internal clock is disrupted, cancer takes advantage — but now we've found a new way to fight back."
When the clock is off, danger is on
Circadian rhythms — our internal 24-hour clock — do far more than regulate sleep. They help coordinate hormone release, tissue repair and the immune system's surveillance.
When disrupted, the body's natural defenses begin to falter.
"The circadian rhythm orchestrates how our tissues function, and how our immune system recognizes danger," Sarkar said. "When that rhythm is disrupted, the consequences can be seriously dangerous."
To investigate these effects, the researchers used two groups of genetically engineered models that develop aggressive breast cancer. One group lived on a normal night-day schedule, while the other lived on a disrupted light cycle that threw off their internal clocks.
The findings, published in Nature group journal Oncogene , were striking.
Typical models develop cancer around the 22-week marker. The circadian-disrupted group, however, showed signs of cancer much earlier — at almost 18 weeks.
Tumors in circadian-disrupted models were also far more aggressive, and far more likely to spread to the lungs, a key indicator of poor outcomes in breast cancer patients.
At the same time, disruption of the models' internal clock suppressed immune defenses, creating a more hospitable environment for cancer growth.
"It wasn't just that tumors grew faster," Sarkar said. "The immune system was actively restrained, creating more favorable conditions for cancer cells to survive and spread."
But the effects weren't just limited to the tumors themselves. The researchers also found that long-term circadian disruption changed the makeup of healthy breast tissue, making it more vulnerable to cancer.
"We observed clear changes in the morphology of the mammary glands, the milk-producing tissue of the breast," Sarkar said.
An immune 'off switch' revealed
To understand how circadian disruptions affected healthy breast tissue and suppressed immune defenses, the researchers took a closer look inside the tumors.
One molecule stood out: leukocyte immunoglobulin-like receptor B4 (LILRB4), a receptor already known to suppress immune responses in several cancers.
Under normal conditions, LILRB4 helps prevent excessive inflammation and protects healthy tissue.
In cancer, however, it can go into overdrive and become dangerous. Think of LILRB4 as the immune system's "off switch."
"LILRB4 acts as an immune checkpoint," Sarkar said. "When we targeted LILRB4, the tumor microenvironment became less immunosuppressive, and even under disrupted circadian conditions, we observed less cancer spread."
Disabling this immune checkpoint helped restore the immune system's ability to fight back, suggesting a new therapeutic angle for treating aggressive breast cancers linked to circadian disruptions.
"When we began to intervene and regulate LILRB4's activity, we observed significantly less cancer metastasis and tumor growth," Sarkar said.
A new context for a known target: Personalized cancer treatment
By experimentally linking circadian disruptions to breast cancer progression, the study opens new doors to targeted therapies for patients whose lifestyles or occupations place them at chronic circadian risk.
"This study shows what can happen when our internal clock is repeatedly disrupted, and how we might begin to repair the damage," Sarkar said.
It also offers some of the strongest evidence that circadian disruption doesn't just correlate with cancer risk, it can actively drive cancer progression.
"The study reframes sleep and timing as powerful players in cancer progression and treatment," Sarkar said.
And in a world that actively runs around the clock, the implications extend far beyond the laboratory. An estimated 12 to 35 percent of Americans work irregular schedules, including night and rotating shifts.
"A significant portion of the population works night or rotating shifts," Sarkar said. "This makes understanding the impact of circadian disruptions on cancer risk incredibly important."
The research team's next big project is to investigate how the effects of chronic circadian disruptions might be reversed in humans, with the aim of improving health outcomes for night-shift workers and others with irregular sleep schedules, like flight attendants and frequent travelers.
"Our next goal is to better understand how we can reverse the effects of circadian disruption and help advance human health with a real-world impact," Sarkar said.
Cancer may keep time — but with monumental discoveries like these, scientists are learning how to take control of the clock.
More information: LILRB4 regulates circadian disruption-induced mammary tumorigenesis via non-canonical WNT signaling pathway. Oncogene 44, 4491–4504 (2025)
DOI 10.1016/j.celbio.2025.100152
https://www.nature.com/articles/s41388-025-03597-5
Journal information: Oncogene
