Fig 1: RANK expression in tumor tissues and TNFRSF11A variations linked to BRCA1-mutated status, risk of breast cancer, and cancer progression. (A) Representative images showing high and low RANK expression in invasive breast cancer tissues from BRCA1 mutation carriers. (B) Representative examples of RANK expression in early epithelial pre-neoplastic lesions in women with BRCA1 mutations. Representative images of a flat epithelial atypia and a typical intraductal papilloma are shown. Scale bars are shown. (C) Graph depicting the TNFRSF11A locus including the variants associated with breast cancer risk in BRCA1 mutation carriers, and regulatory evidence from the ENCODE project and human mammary epithelial cells (HMECs). The rs884205 variant and the two in linkage disequilibrium and analyzed in TCGA dataset are marked in red. The exons are marked by blue-filled rectangles and the direction of transcription is marked by arrows in the gene structure. The chromosome 18 positions (base pairs (bp)) and linkage disequilibrium (r2) from a HapMap CEU panel are also shown. (D) Kaplan-Meier survival plots for the indicated TNFRSF11A genotypes (A and B represent the major and minor allele, respectively) in ER-negative and ER-positive breast tumors using TCGA data. (E) Gene Set Expression Analysis (GSEA) graphical output showing the positive correlation between the gene expression in tumors with the minor genotype (associated with poorer prognosis in ER-negative human breast cancer) and gene sets that characterize RANK overexpression in mammary epithelial cells of mice at 8, 24 or 72 h (GSE66174). All three sets were found to be significantly associated (P < 0.01); the score distribution curves overlap. The gene rank corresponds to the 8 h time point and the GSEA enrichment scores are shown26.