Circadian Rhythm, Immune System, and Breast Cancer: Working Night Shifts Increases Cancer Risk
- Jan 13
- 4 min read
This study shows that disruption of the biological clock can favor the development of aggressive breast cancer by altering the structure of the mammary gland and weakening the immune system. Disruption of the circadian rhythm increases the expression of a molecule that suppresses immunity, facilitating tumor progression and metastasis. Blocking this pathway may be a promising therapeutic strategy.
The human body functions according to an "internal clock," called the circadian clock, which organizes various biological functions throughout the day and night. This clock regulates when certain genes are activated or deactivated, influencing metabolism, organ function, the immune system, and overall health.
When this natural rhythm is disrupted, as happens in people who work night shifts, rotating schedules, or frequently travel between time zones, the body begins to function out of sync, which can have consequences for health.
Several studies show that this disruption of the circadian rhythm is associated with a higher risk of chronic diseases, including metabolic disorders, cardiovascular diseases, and various types of cancer, such as lung, colon, and breast cancer.
In the United States, a significant portion of the population works irregular hours, making this a relevant public health issue. In the case of breast cancer, for example, women who work shifts, such as nurses, have a significantly higher risk of developing the disease.
The circadian clock operates within cells through a system of mutually regulating genes, maintaining a balance between activation and inhibition throughout the day. When this system malfunctions, the expression of these genes can become disorganized. In human tumors, this dysregulation is common and suggests that the circadian clock normally plays a protective role against cancer development.
This study investigated how chronic disruption of the circadian rhythm specifically affects the mammary gland and the development of an aggressive type of breast cancer known as triple-negative breast cancer.
Using an experimental model in mice, the researchers observed that circadian rhythm dysregulation alters the normal structure of the mammary gland, increases the spread of cancer to the lungs, and creates a tumor environment that weakens the immune system's response.
One of the key findings was the identification of a molecule called LILRB4, which acts by suppressing the immune response. Disruption of the circadian rhythm increased the expression of this molecule, favoring tumor growth and metastasis. When researchers blocked LILRB4 through an immunotherapy approach, they observed a reduction in immunosuppression and lung metastasis.
These results suggest that disrupting the circadian rhythm may drive more aggressive cancers by interfering with immunity and that LILRB4 may be a promising target for future therapies.
This figure illustrates how breast tumor cells differ from healthy cells in terms of cellular identity and the functioning of the “biological clock.” In the upper panels (A and B), each point represents an individual cell, grouped according to its type and whether it is cancerous (malignant) or non-cancerous. It is possible to see that cancerous cells form distinct groups, indicating that they behave differently from the normal cells surrounding the tumor. Panel C shows that a higher proportion of tumor cells exhibit signs of circadian rhythm disruption compared to non-malignant cells. In panel D, it is observed that central genes of the biological clock, responsible for regulating daily cycles of cellular activity, show altered levels in tumor cells, suggesting that this system is dysregulated in cancer. Finally, panel E compares the expression of these genes in tumor tissue and surrounding healthy tissue, revealing that the tumor loses normal control of the biological clock. Taken together, the figure illustrates that the disruption of the circadian rhythm is not merely a secondary effect of cancer, but an important characteristic of tumor cells, possibly contributing to their aggressive growth and ability to spread.
Taken together, these findings reinforce the idea that the biological clock is not only a regulator of sleep, but a central element in protecting cellular and immune health. Chronic disruption of the circadian rhythm creates a favorable environment for the development of more aggressive cancers by disrupting gene expression, altering tissue structure, and weakening the defenses of the immune system.
By identifying the LILRB4 molecule as a link between the disruption of the biological rhythm and the progression of breast cancer, the study opens new perspectives for prevention and treatment strategies, especially for people exposed to irregular schedules for long periods.
These results highlight the importance of considering the biological rhythm as a relevant factor in public health and in the development of more targeted and effective cancer therapies.
READ MORE:
LILRB4 regulates circadian disruption-induced mammary tumorigenesis via non-canonical WNT signaling pathway
Olajumoke Ogunlusi, Mrinmoy Sarkar, Kayla Carter, Arhit Chakrabarti, Devon J. Boland, Tristan Nguyen, James Sampson, Christian Nguyen, Danielle Fails, Yava Jones-Hall, Loning Fu, Gus Wright, Da Mi Kim, James J. Cai, Bani Mallick, Alex C. Keene, Jeff R. Jones, and Tapasree Roy Sarkar
Oncogene, volume 44, pages 4491–4504 (2025)
Abstract|:
Epidemiological studies have shown that circadian rhythm disruption (CRD) is associated with the risk of breast cancer. However, the role of CRD in mammary gland morphology and aggressive basal mammary tumorigenesis and the molecular mechanism underlying CRD-induced carcinogenesis remain unknown. To investigate the effect of CRD on aggressive tumorigenesis, a genetically engineered mouse model of aggressive breast cancer was used. The impact of CRD on the tumor microenvironment was investigated using the tumors from LD12:12 and CRD mice via scRNA-seq, flow cytometry, multiplexing immunostaining, and realtime PCR. The effect of LILRB4-immunotherapy on CRD-induced tumorigenesis was also investigated. Here we investigated and identified the impact of CRD on basal tumorigenesis and mammary gland morphology. We found that chronic CRD disrupted mammary gland morphology, increased lung metastasis, and induced an immunosuppressive tumor microenvironment by enhancing LILRB4 expression. Furthermore, targeted immunotherapy against LILRB4 reduced CRD-induced immunosuppressive microenvironment and lung metastasis. Finally, we showed that LILRB4 regulates CRD-induced mammary tumorigenesis via a non-canonical WNT signaling pathway. These findings identify and implicate LILRB4 as a link between CRD and aggressive mammary tumorigenesis and establish the potential role of the targeted LILRB4a immunotherapy as an inhibitor of CRD-induced lung metastasis.
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