TY - JOUR
T1 - Cyclin E1 overexpression triggers interferon signaling and is associated with antitumor immunity in breast cancer
AU - Yu, Shibo
AU - Stappenbelt, Chantal
AU - Chen, Mengting
AU - Dekker, Mirte
AU - Bhattacharya, Arkajyoti
AU - van der Sluis, Tineke
AU - Zwager, Mieke C
AU - Schröder, Carolien P
AU - Fehrmann, Rudolf S N
AU - van Vugt, Marcel A T M
AU - van der Vegt, Bert
N1 - © Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.
PY - 2025/3/17
Y1 - 2025/3/17
N2 - BACKGROUND: Cyclin 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.METHODS: Tissue 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.RESULTS: Increased 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. CONCLUSIONS: Our 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.
AB - BACKGROUND: Cyclin 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.METHODS: Tissue 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.RESULTS: Increased 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. CONCLUSIONS: Our 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.
KW - Humans
KW - Cyclin E/metabolism
KW - Female
KW - Breast Neoplasms/immunology
KW - Interferons/metabolism
KW - Signal Transduction
KW - Oncogene Proteins/metabolism
KW - Tumor Microenvironment
KW - Cell Line, Tumor
KW - Immunotherapy/methods
U2 - 10.1136/jitc-2024-009239
DO - 10.1136/jitc-2024-009239
M3 - Article
C2 - 40101803
SN - 2051-1426
VL - 13
JO - Journal for immunotherapy of cancer
JF - Journal for immunotherapy of cancer
IS - 3
M1 - e009239
ER -