Abstract:
Background: 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 mechanisms underlying CRD and cancer risk remain unknown.
Methods: 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 tumor microenvironment was investigated using the tumors from LD12:12 and CRD mice via scRNA seq. ScRNA seq was substantiated by multiplexing immunostaining, flow cytometry and realtime PCR. The effect of LILRB4-immunotherapy on CRD-induced tumorigenesis was also investigated. Here we identified the impact of CRD on basal tumorigenesis and mammary gland morphology and identified the role of LILRB4 on CRD-induced lung metastasis.
Results: We found that chronic CRD disrupted mammary gland morphology and increased lung metastasis and induced an immunosuppressive tumor microenvironment by enhancing LILRB4a expression. Furthermore, targeted immunotherapy against LILRB4 reduced CRD-induced immunosuppressive microenvironment and lung metastasis.
Conclusions: These findings identify and implicate LILRB4a as a link between CRD and aggressive mammary tumorigenesis and establishes the potential role of the targeted LILRB4a immunotherapy as an inhibitor of CRD-induced lung metastasis.
Audience Take Away Notes:
According to the Occupational Health Supplements survey (NIOSH, 2015), in the USA, 27%of the working population is involved in shift work(13). Studies showed that women who work the night shift had an increased risk of skin cancer, breast cancer, and gastrointestinal cancer. Therefore, it is imperative to understand the effect of circadian disruption on women's health.
