31 Loss of P53 drives systemic neutrophilic inflammation in breast cancer

Abstract

Introduction Metastasis remains the primary cause of death for breast cancer patients. The metastatic cascade is largely regulated by interactions between cancer cells and their microenvironment. Using a genetically engineered mouse model (GEMM) for breast cancer, we have previously shown that mammary tumours elicit a systemic inflammatory cascade, involving γδ T cells and neutrophils, which promotes metastasis. Breast cancer is a heterogeneous disease, and it is unknown whether and how the genetic make-up of primary tumours influences pro-metastatic inflammation. Therefore, we set out to dissect the cancer cell-intrinsic genetic events that activate systemic inflammation in breast cancer. Material and methods We make use of a panel of 16 GEMMs for breast cancer with different tissue-specific genetic modifications driving tumorigenesis, which recapitulate all subtypes of human breast cancer. Results and discussions We observed increased levels of neutrophil-activating cytokines and elevated numbers of neutrophils in mice bearing p53-deficient mammary tumours, compared to mice with p53-proficient tumours. To identify the cancer cell-derived factors underlying enhanced systemic inflammation upon p53 loss, we compared the transcriptome profiles of p53-deficient with p53-proficient mammary tumours. Consistent with the enhanced neutrophil activation, we observed significant changes in various immune-related pathways in p53-deficient tumours. Using CRISPR/Cas9-based technologies in GEMM-derived cancer cell lines, we investigated the influence of candidate genes that are consistently up-regulated in Trp53–/–tumours on the cellular crosstalk in the tumour microenvironment. Conclusion Together, these data reveal that cancer cell-intrinsic loss of p53 dictates the communication between cancer cells and their microenvironment, leading to activation of a systemic neutrophilic inflammatory cascade.