a, Total and cKIT+ neutrophil frequencies in lungs of vehicle-treated (n = 7) or LGK974-treated (n = 4) K14-cre;Cdh1F/F;Trp53F/F (KEP) mice using indicated 5-day short-term treatment schedule. Representative flow cytometry plots are shown. b, Frequency of IL-17A-producing γδ T cells in lungs of vehicle-treated (n = 6) or LGK974-treated (n = 4) KEP mice. Representative flow cytometry plots are shown. c, Kinetics of circulating neutrophils in vehicle- or LGK974-treated KEP mice using indicated long-term treatment schedule, shown as frequency at indicated tumour volumes (n = 8 per group). d, RT–qPCR analysis of Porcn expression in end-stage bulk tumour (n = 5 per group). Data are normalized to control shRNA (shControl) and represents an average of two technical replicates. e, Correlation of total neutrophil levels in the circulation with the expression of Porcn in WEA;Trp53−/−;shControl and WEA;Trp53−/−;shPorcn whole tumour lysate (n = 5 per group). f, Correlation of cKIT+ neutrophil levels in circulation with expression of Porcn in WEA;Trp53−/−;shControl and WEA;Trp53−/−;shPorcn whole tumour lysate (n = 5 per group). g, Correlation of Porcn expression and Il1b expression in bulk WEA;Trp53−/−;shControl (blue) and WEA;Trp53−/−;shPorcn tumours (grey) (n = 5 per group). Data represent an average of two technical replicates. h, Spleen area in mice with WEA;Trp53−/−;shControl (blue) and WEA;Trp53−/−;shPorcn tumours (grey) tumours at end stage (n = 5 per group). i, Growth kinetics of orthotopically transplanted KEP mammary tumours, treated with vehicle (n = 12) or LGK974 (n = 15). Each line represents an individual mouse. j, Growth kinetics of orthotopically injected Trp53+/+ and Trp53−/− WEP cells, treated with vehicle or LGK974. Each line represents an individual mouse (n = 9 per group). k, Schematic representation of the findings of this study: loss of p53 in breast cancer cells triggers secretion of WNT ligands to activate tumour-associated macrophages. This stimulates systemic expansion and activation of neutrophils, which we have previously shown to be immunosuppressive5, thus driving metastasis. All data are mean ± s.e.m. P values are determined by two-tailed Mann–Whitney U-test (a–d, h), linear regression analysis (e–g) and area under the curve of average growth curves, followed by two-tailed Welch’s t-test (i, j). Source data