Cyclin E1 overexpression triggers interferon signaling and is associated with antitumor immunity in breast cancer

BackgroundCyclin E1 overexpression drives oncogenesis in several cancers through deregulation of DNA replication and induction of genomic instability, which may potentially trigger immune signaling via cytoplasmic DNA. However, the effects of cyclin E1 overexpression on tumor immunity and its effect...

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Published in:Journal for immunotherapy of cancer Vol. 13; no. 3; p. e009239
Main Authors: Yu, Shibo, Stappenbelt, Chantal, Chen, Mengting, Dekker, Mirte, Bhattacharya, Arkajyoti, van der Sluis, Tineke, Zwager, Mieke C, Schröder, Carolien P, Fehrmann, Rudolf S N, van Vugt, Marcel A T M, van der Vegt, Bert
Format: Journal Article
Language:English
Published: England BMJ Publishing Group Ltd 17.03.2025
BMJ Publishing Group LTD
BMJ Publishing Group
Subjects:
Breast Cancer
Breast Neoplasms - genetics
Breast Neoplasms - immunology
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cell cycle
Cell Line, Tumor
Cyclin E - genetics
Cyclin E - metabolism
Cyclin-dependent kinases
Cytoplasm
DNA damage
Female
Flow cytometry
Gene expression
Humans
Immunotherapy
Immunotherapy biomarkers
Interferon
Interferons - metabolism
Kinases
Kruskal-Wallis test
Medical prognosis
Oncogene Proteins - genetics
Oncogene Proteins - metabolism
Patients
Regression analysis
Signal Transduction
Survival analysis
Taxonomy
Tumor Microenvironment - immunology
Tumors
Breast Cancer
Immunotherapy
ISSN:2051-1426, 2051-1426
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Summary:BackgroundCyclin E1 overexpression drives oncogenesis in several cancers through deregulation of DNA replication and induction of genomic instability, which may potentially trigger immune signaling via cytoplasmic DNA. However, the effects of cyclin E1 overexpression on tumor immunity and its effects on the response to immune checkpoint inhibitors remain largely unclear.MethodsTissue microarrays and clinical outcomes of 398 patients with breast cancer were analyzed to explore the correlation between cyclin E1 expression, patient survival, and immune cell infiltration using immunohistochemistry. Genomic data from publicly available data sets and three clinical trials evaluating immunotherapy were assessed to measure the impact of cyclin E1 expression on the immune cells in the tumor microenvironment and response to immunotherapy in patients with breast cancer. In addition, breast cancer cell lines with inducible cyclin E1 overexpression were employed to analyze the effects of cyclin E1 on inflammatory signaling.ResultsIncreased cyclin E1 expression in breast cancer was positively correlated with immune cell infiltration, including T cells, B cells, and natural killer cells, and activation of interferon-related pathways. Importantly, higher cyclin E1 expression or CCNE1 amplification was associated with better response to immunotherapy in three clinical trials. Mechanistically, cyclin E1 overexpression resulted in micronuclei formation and activation of innate immune signaling, resulting in increased immune cell migration.ConclusionsOur data show that cyclin E1 overexpression associate with antitumor immunity through activation of innate inflammatory signaling and warrants investigation into amplification or overexpression of cyclin E1 in identifying patients with breast cancer eligible for immunotherapy.
Bibliography:Original research
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ISSN:2051-1426
2051-1426
DOI:10.1136/jitc-2024-009239