Figure 4. Mutant p53 promotes β-catenin stabilization and activity through FOXA1.

A, IPA analysis results of top upstream regulators of genes differentially expressed in tumors derived from KP^wm/+C mice relative to KP^fl/+C mice. B, Enriched transcription factors associated with Wnt/β-catenin signaling in KP^wm/+C tumors. C, β-catenin levels measured in tumors derived from KP^wm/+C and KP^fl/+C mice. D, Effect of mutant p53 knockdown on β-catenin levels in murine and human PDAC. E, β-catenin activity following mutant p53 knockdown as measured by the TOPFlash luciferase reporter system (TLRS). F, The effect of β-catenin knockdown on PDAC cell migration/invasion, with and without mutant p53R172H. G, β-catenin levels following ectopic mutant p53R172H expression in p53 null, KP^flC cells (KP^flC-p53R172H) and heterotopic engraftment into immunodeficient mice. H, Immunohistochemical evaluation and quantification of β-catenin in KP^flC (n=5) and KP^flC-p53R172H (n=5) tumors. I, The effect of FOXA1 knockdown on β-catenin levels in murine and human PDAC. J, Levels of β-catenin following Foxa1 overexpression in two p53-null, KP^flC cell lines (KP^flC-Foxa1). K, β-catenin levels were measured in whole tumor lysates following engraftment of KP^flC-Foxa1 cells into nude mice (n=5) along with vector controls (n=5). L, Immunohistochemical evaluation and quantification of Foxa1 in KP^flC (n=5) and KP^flC-Foxa1 (n=5) tumors. M, β-catenin activity (TLRS) following FOXA1 knockdown. N, β-catenin activity (TLRS) following FOXA1 overexpression. (E, G, H, L, M, N), Data are mean±s.d. and P values determined by unpaired two-tailed t-tests. (F), P value calculated by one-way ANOVA.