Language

English

Publication Date

12-1-2025

Journal

Oncogene

DOI

10.1038/s41388-025-03597-5

PMID

41102383

PMCID

PMC12602328

PubMedCentral® Posted Date

10-16-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Animals, Female, Wnt Signaling Pathway, Mice, Tumor Microenvironment, Carcinogenesis, Receptors, Immunologic, Circadian Rhythm, Membrane Glycoproteins, Lung Neoplasms, Humans, Mammary Neoplasms, Experimental, Breast cancer, Biomarkers

Published Open-Access

yes

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