Fig. 1. MRE11 suppresses breast tumorigenesis driven by MYC overexpression and p53 deficiency.

a, Fraction of genome altered (left), and RPPA signals for pCHK2(T68) (middle) and pCHK1(S345) (right) in TCGA breast cancers stratified by MYC amplification (MYC^amp) and TP53 alterations (TP53^mut/deep-del), analysed by one-way analysis of variance (ANOVA). Box plots show the median, the 25th to 75 percentiles and range. N indicates the number of independent tumours from the TCGA-BRCA Pan-Cancer Atlas dataset. P values (left to right): fraction of genome altered, P = 0.0251, P < 0.0001, P < 0.0001; pCHK2, P = 0.9999, P < 0.0001, P < 0.0001; pCHK1, P = 0.9999, P = 0.0003, P < 0.0001. b, Schematic of the transgenic breast cancer model used for the DDR-CRISPR sgRNA library screen. c, Sections from a non-injected mammary gland (top) and a mammary gland 4 months after DDR-CRISPR lentiviral injection (bottom) and stained with haematoxylin and eosin. d, Kaplan–Meier tumour-free survival curve after injection with the DDR-CRISPR library. e, Normalized gene z scores relative to control. f, Bar plot depicting the most commonly targeted DDR genes. g, Kaplan–Meier tumour-free survival curves of R26^{LSL-cas9/LSL-Myc};Trp53^fl/fl female mice after mammary intraductal injection with Cre-sgControl (n = 24 biologically independent animals) or Cre-sgMre11 (n = 42 biologically independent animals), analysed by two-tailed log-rank test. h, Sections of mammary tumours induced by Cre-sgControl or Cre-sgMre11 (bottom) stained with haematoxylin and eosin. i, Spider plot (left) of tumour growth after initial palpation of mammary tumours and bar plot (right) of time from palpation to tumour end point. sgControl versus sgMre11, P = 0.0033. j, Representative immunohistochemistry images (left and middle) and quantification (right) of histone H3S10ph. sgControl (n = 3 biologically independent tumours) versus sgMre11 (n = 3 biologically independent tumours), P = 0.01. Graph depicts mean ± s.e.m. Grouped comparisons analysed by unpaired, two-tailed t-test. NS, not significant, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Scale bar, 200 µm (h,j), 1 mm (c).

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