Working night shifts, frequently flying across time zones, or maintaining an irregular sleep schedule does more than just leave individuals exhausted; it significantly increases the risk of aggressive breast cancer. The precise mechanisms behind this phenomenon have long puzzled scientists, but a groundbreaking study from Texas A&M University College of Arts and Sciences has begun to unravel the mystery.
Led by Dr. Tapasree Roy Sarkar, the research highlights how disruptions in circadian rhythms alter mammary gland structures and weaken immune defenses, suggesting a new approach to counter these effects. “Cancer keeps time,” Sarkar stated. “If your internal clock is disrupted, cancer takes advantage — but now we’ve found a new way to fight back.”
Understanding Circadian Rhythms and Their Impact
Circadian rhythms, our body’s internal 24-hour clock, regulate much more than sleep. They coordinate hormone release, tissue repair, and the immune system’s vigilance. When these rhythms are disrupted, the body’s natural defenses falter.
“The circadian rhythm orchestrates how our tissues function and how our immune system recognizes danger,” Sarkar explained. “When that rhythm is disrupted, the consequences can be seriously dangerous.”
To explore these effects, the researchers studied two groups of genetically engineered models predisposed to aggressive breast cancer. One group followed a normal night-day schedule, while the other experienced a disrupted light cycle, throwing off their internal clocks.
Striking Findings from the Study
The results, published in the journal Oncogene, were compelling. Typically, cancer in these models develops around the 22-week mark. However, the circadian-disrupted group showed signs of cancer nearly four weeks earlier, at around 18 weeks.
Tumors in the circadian-disrupted models were not only more aggressive but also more likely to metastasize to the lungs, a critical indicator of poor outcomes in breast cancer patients. The disruption also suppressed immune defenses, creating a hospitable environment for cancer growth.
“It wasn’t just that tumors grew faster,” Sarkar noted. “The immune system was actively restrained, creating more favorable conditions for cancer cells to survive and spread.”
Moreover, the researchers discovered that long-term circadian disruption altered the makeup of healthy breast tissue, increasing its vulnerability to cancer.
The Role of LILRB4: An Immune ‘Off Switch’
To understand how circadian disruptions affected healthy breast tissue and immune defenses, the researchers examined the tumors more closely. They identified a key molecule: leukocyte immunoglobulin-like receptor B4 (LILRB4), a receptor known to suppress immune responses in various cancers.
Under normal conditions, LILRB4 prevents excessive inflammation and protects healthy tissue. However, in cancer, it can become overactive and dangerous, acting as the immune system’s “off switch.”
“LILRB4 acts as an immune checkpoint,” Sarkar explained. “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 combat cancer, suggesting a new therapeutic angle for treating aggressive breast cancers linked to circadian disruptions.
Implications for Personalized Cancer Treatment
By experimentally linking circadian disruptions to breast cancer progression, the study opens new avenues for 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 provides strong evidence that circadian disruption doesn’t just correlate with cancer risk; it actively drives cancer progression.
“The study reframes sleep and timing as powerful players in cancer progression and treatment,” Sarkar stated.
In a world that never sleeps, 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 noted. “This makes understanding the impact of circadian disruptions on cancer risk incredibly important.”
The research team’s next major project aims to investigate how the effects of chronic circadian disruptions might be reversed in humans, with the goal of improving health outcomes for night-shift workers and others with irregular sleep schedules, such as 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 Read more
