Circadian rhythm disruption alters mammary gland morphology and accelerates cold aggressive tumorigenesis through a LILRB4-dependent pathway

Epidemiological studies have shown that circadian rhythm disruption (CRD) caused by shift work or frequent jet lag is associated with the risk of breast cancer development. However, the role of CRD in mammary gland morphology and aggressive mammary tumorigenesis and the molecular mechanisms underlying CRD and cancer risk remain unknown. We found that chronic CRD disrupted mouse mammary gland morphology and increased tumor burden and lung metastasis in a genetically engineered mouse model of aggressive breast cancer and induced an immunosuppressive tumor microenvironment by enhancing leukocyte immunoglobulin-like receptor 4a (LILRB4a or LILRB4) expression. Moreover, CRD increased the M2 macrophage (anti-inflammatory) and regulatory T-cell populations but decreased the M1 macrophage (proinflammatory) populations. These findings identify and implicate LILRB4a as a link between CRD and aggressive mammary tumorigenesis.